Affinage

PTF1A

Pancreas transcription factor 1 subunit alpha · UniProt Q7RTS3

Length
328 aa
Mass
35.0 kDa
Annotated
2026-06-10
92 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTF1A (p48) is a lineage-determining basic helix-loop-helix transcription factor that functions as the cell-specific DNA-binding subunit of the trimeric PTF1 complex, which it forms with a class I E-protein and either RBPJ or RBPJL (PMID:9851981, PMID:16201968). Through this complex it directs two distinct developmental programs: specification and maintenance of pancreatic exocrine (acinar) identity, and specification of GABAergic/inhibitory over glutamatergic/excitatory neuronal fate across the cerebellum, spinal cord, retina, brainstem, and hypothalamus (PMID:16039563, PMID:16291784, PMID:24733890). In the pancreas, PTF1A is induced in foregut endoderm by aortic endothelial signals and is required to specify pancreatic fate from undifferentiated progenitors, which otherwise adopt duodenal fates (PMID:12185368, PMID:14736742); it then acts as a cross-repressive determinant that drives acinar over endocrine programs and, in the adult, directly maintains digestive-enzyme, UPR-surveillance, and acinar transcription-factor network genes (PMID:20627083, PMID:27697859). Loss of PTF1A in adult acinar cells triggers ER-stress apoptosis, acinar-to-ductal metaplasia, and a KRAS-permissive state, establishing it as a pancreatic tumor suppressor (PMID:26151762, PMID:30361559). PTF1A binds direct genomic targets including Pdx1, Mnx1, Nkx6.1, Onecut1, Dll1, Neurog2, Prdm13, Nephrin and Neph3, and sustains its own expression through PTF1-complex autoregulatory enhancers that set the protein levels needed for correct cell-fate output (PMID:17403901, PMID:22232429, PMID:22096075, PMID:19641016, PMID:24370451, PMID:19887377, PMID:18606784, PMID:32241803). Its binding specificity is constrained by tissue-specific open chromatin and cooperating factors such as Foxa2 (PMID:23754747). PTF1A activity requires p/CAF-mediated acetylation at Lys200 and is antagonized by HES/Hey proteins, Id3, and ICAT through direct protein interactions, with Id3 controlling E47-dependent nuclear localization (PMID:18834332, PMID:16201968, PMID:20830706, PMID:23339455). Human truncating mutations and enhancer mutations cause pancreatic and cerebellar agenesis or isolated pancreatic agenesis (PMID:15543146, PMID:24212882).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1998 High

    Established that PTF1A is an essential cell-type-specific transcription factor for the exocrine pancreatic lineage, defining its core developmental requirement.

    Evidence Null allele knockout in mice with histological analysis of pancreatic tissue

    PMID:9851981

    Open questions at the time
    • Did not resolve whether the defect was specification, differentiation, or proliferation
    • No direct target genes identified at this stage
  2. 2002 High

    Showed PTF1A acts upstream in multipotent progenitors to specify pancreatic versus duodenal fate, broadening its role beyond exocrine differentiation.

    Evidence Cre lineage tracing, Ptf1a null analysis, and Pdx1 transgene rescue in mice

    PMID:12185368

    Open questions at the time
    • Direct PTF1A targets driving fate choice not yet defined
    • Inductive signals turning on Ptf1a unknown
  3. 2004 High

    Linked PTF1A to human disease and mapped a functionally critical C-terminal domain beyond the bHLH, while extending its requirement to the cerebellum.

    Evidence Positional cloning of truncating mutations, deletion-mutant reporter assays, mouse neuropathology

    PMID:15543146

    Open questions at the time
    • Molecular role of the C-terminal domain not defined
    • Neuronal targets unidentified
  4. 2004 High

    Identified the upstream inductive signal, showing aortic endothelium triggers PTF1A expression to initiate dorsal pancreatic budding.

    Evidence Tissue recombination with Flk1-/- endothelium-deficient embryos and in situ hybridization

    PMID:14736742

    Open questions at the time
    • Molecular identity of the endothelial signal not defined
    • Transcriptional intermediaries linking signal to Ptf1a unknown
  5. 2005 High

    Generalized PTF1A as a determinant of GABAergic over glutamatergic neuronal fate, demonstrating both necessity and sufficiency in CNS progenitors.

    Evidence Cerebelless and null mutant analysis, lineage tracing, and ectopic expression by electroporation in cerebellum and spinal cord

    PMID:16039563 PMID:16291784

    Open questions at the time
    • Direct neural target genes not yet identified
    • Whether the same PTF1 complex operates in neurons not yet shown
  6. 2006 High

    Defined the biochemical complex and its negative regulators, establishing PTF1A as a DNA-binding subunit inhibited by direct HES/Hey binding.

    Evidence Co-IP, yeast two-hybrid, GST pulldown, and reporter assays mapping the trimeric PTF1 complex and HES interaction domains

    PMID:16201968

    Open questions at the time
    • In vivo relevance of HES inhibition to specific tissues not tested
    • Stoichiometry and structure of the complex unresolved
  7. 2007 High

    Extended PTF1A's inhibitory-neuron specification role to the retina and climbing-fiber neurons and placed it downstream of Foxn4.

    Evidence Conditional knockout, lineage tracing, fate mapping, and immunohistochemistry in retina and hindbrain

    PMID:17075007 PMID:17301087 PMID:17928434

    Open questions at the time
    • Direct retinal/hindbrain targets not defined here
    • Mechanism of partial trans-differentiation unclear
  8. 2008 High

    Demonstrated direct genomic occupancy and autoregulation, showing PTF1A binds the Pdx1 area III and its own enhancer to lock in acinar identity.

    Evidence ChIP from embryonic pancreas, transgenic reporters with site mutagenesis, EMSA, and cell transfection

    PMID:17403901 PMID:18606784

    Open questions at the time
    • Genome-wide target set not yet defined
    • Quantitative contribution of autoregulation to cell-fate thresholds unresolved
  9. 2008 High

    Established PTF1A as a cross-repressive lineage switch with Nkx6 factors operating within a defined competence window.

    Evidence Reciprocal gain- and loss-of-function mouse models and lineage tracing

    PMID:18634777 PMID:20627083

    Open questions at the time
    • Mechanism of the competence window not defined
    • Direct repressed endocrine targets not enumerated
  10. 2009 High

    Identified the first direct neural targets and the regulatory grammar controlling Ptf1a levels, unifying its pancreatic and neural mechanisms.

    Evidence ChIP from neural tube, in vivo gain/loss of function in chick and mouse, reporter mutagenesis for Neurog2, Nephrin, Neph3 and autoregulatory elements

    PMID:19641016 PMID:19741120 PMID:19887377

    Open questions at the time
    • Full neural target repertoire incomplete
    • How initiation versus maintenance enhancers are switched not resolved
  11. 2009 High

    Showed PTF1A activity is post-translationally gated by p/CAF acetylation at Lys200, required for full transcriptional output.

    Evidence Co-IP from acinar cells, ChIP at target promoters, and K200R mutagenesis with reporter assays

    PMID:18834332

    Open questions at the time
    • Deacetylase counter-regulator not identified
    • In vivo phenotype of acetylation-defective PTF1A not tested
  12. 2010 Medium

    Defined Id3 as a regulator of PTF1A subcellular localization, linking gastrin signaling to cytoplasmic mislocalization of PTF1A.

    Evidence Co-IP, Id3 siRNA, and subcellular imaging in AR4-2J acinar cells

    PMID:20830706

    Open questions at the time
    • Single lab, two-method study without in vivo validation
    • Direct nuclear import machinery not identified
  13. 2011 High

    Uncovered a Ptf1a-Dll1-Hes1 feedback circuit promoting progenitor proliferation, and showed continuous PTF1A is required to maintain acinar identity.

    Evidence Genetic epistasis mouse models, BrdU proliferation assays, and zebrafish lineage tracing under Ptf1a antagonism

    PMID:21497092 PMID:22096075

    Open questions at the time
    • The zebrafish maintenance result is single-lab
    • How the circuit balances proliferation versus differentiation not fully resolved
  14. 2012 High

    Mapped the genome-wide pancreatic target network, establishing PTF1A as a direct upstream activator of the progenitor transcription-factor program.

    Evidence ChIP-seq and RNA profiling from pancreatic progenitors with reporter validation of Mnx1, Pdx1, Nkx6.1, Onecut1

    PMID:22232429 PMID:22372950

    Open questions at the time
    • Rbms3 post-transcriptional control is single-lab
    • Hierarchy among co-regulated targets not resolved
  15. 2013 High

    Explained tissue-specific binding and identified a key neural effector, showing chromatin accessibility and Foxa2 constrain PTF1A while Prdm13 enforces inhibitory fate downstream.

    Evidence ChIP-seq in pancreas and neural tube, open-chromatin analysis, co-transfection synergy, and gain/loss of function for Prdm13 in Xenopus and mouse

    PMID:23339455 PMID:23754747 PMID:24370451

    Open questions at the time
    • Determinants directing PTF1A to tissue-specific open chromatin not fully defined
    • ICAT regulation tested largely in vitro
  16. 2013 High

    Established that ectopic or mislocalized PTF1A expression causes disease, and that human enhancer mutations are a major cause of isolated pancreatic agenesis.

    Evidence KO/KI mouse models of an ETn insertion (Danforth's short tail) and whole-genome sequencing plus enhancer reporter assays in human pancreatic agenesis

    PMID:23436999 PMID:23437000 PMID:24212882

    Open questions at the time
    • Endogenous factors normally restraining ectopic Ptf1a expression not defined
    • How the distal enhancer integrates upstream inputs incomplete
  17. 2015 High

    Defined PTF1A as a pancreatic tumor suppressor whose loss creates a KRAS-permissive metaplastic state.

    Evidence Conditional knockout, RNA-seq, KRAS combination mouse models, and human PanIN tissue analysis

    PMID:25966682 PMID:26151762

    Open questions at the time
    • Direct transcriptional targets mediating tumor suppression not fully mapped
    • Whether restoring PTF1A reverses metaplasia not tested
  18. 2016 High

    Showed adult acinar identity is actively maintained by direct PTF1A control of digestive-enzyme, UPR, and transcription-factor network genes.

    Evidence RNA-seq and ChIP-seq from adult pancreas after conditional Ptf1a depletion

    PMID:27697859

    Open questions at the time
    • Order of events from PTF1A loss to metaplasia not resolved
    • Cofactor changes accompanying maintenance not defined
  19. 2018 High

    Demonstrated PTF1A alone reprograms fibroblasts into induced neural stem cells via Notch-independent Rbpj interaction, revealing potent fate-instructive capacity.

    Evidence Direct reprogramming of mouse and human fibroblasts, Co-IP, transcriptomics, and transplantation

    PMID:30030434

    Open questions at the time
    • Genome-wide reprogramming targets not yet mapped at this stage
    • Efficiency-limiting cofactors unknown
  20. 2018 Medium

    Linked acute PTF1A loss to ER-stress apoptosis and extended its role to hypothalamic sexual differentiation.

    Evidence Conditional homozygous knockout with EM and UPR western blots; conditional KO with behavioral and Kiss1 expression analysis

    PMID:29972793 PMID:30361559

    Open questions at the time
    • Both findings are single-lab
    • Direct PTF1A targets in the UPR and hypothalamic programs not defined
  21. 2020 High

    Showed autoregulatory feedback sets the PTF1A dose required to specify specific inhibitory interneuron subtypes that gate itch and movement-related sensory information.

    Evidence Targeted cis-regulatory mutations, neuron ablation/chemogenetics, anatomical tracing, and behavioral testing in mice

    PMID:32241803 PMID:33238109

    Open questions at the time
    • Quantitative dose-response between PTF1A levels and subtype output not fully defined
    • Circuit downstream of these neurons partially characterized
  22. 2024 Medium

    Began defining how PTF1A reorganizes chromatin architecture, binding subTAD boundaries and modulating enhancers during fate transitions.

    Evidence Hi-C, ChIP-seq (PTF1A, CTCF, H3K27ac), and RNA-seq multiomics during fibroblast-to-NSC transdifferentiation

    PMID:39537822

    Open questions at the time
    • No functional mutagenesis of specific boundaries
    • Causality between boundary binding and gene activation not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PTF1A protein dosage, post-translational modification, cofactor availability, and 3D chromatin remodeling are integrated to select between the pancreatic and neural transcriptional programs in different tissues remains unresolved.
  • Structural basis of PTF1 trimer assembly and DNA recognition undefined
  • Determinants that pioneer or constrain PTF1A access to tissue-specific chromatin incompletely mapped
  • Mechanism switching PTF1A between RBPJ- and RBPJL-containing complexes not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 2
Partners
FOXA2HES1ICATID3P/CAFRBPJRBPJL
Complex memberships
PTF1 complex (PTF1A-E protein-RBPJ/RBPJL)

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PTF1A (p48) is the cell-specific DNA-binding subunit of the hetero-oligomeric PTF1 transcription factor complex that directs expression of exocrine pancreatic genes; null mutation in mice abolishes exocrine pancreatic tissue, establishing PTF1A as required for exocrine cell lineage differentiation and/or proliferation. Gene knockout (null allele generation in mice), histological and molecular analysis of pancreatic tissue Genes & development High 9851981
2002 PTF1A is expressed in multipotent pancreatic progenitors (progenitors of ducts, exocrine, and endocrine cells) at early stages of pancreas development; inactivation of Ptf1a causes pancreatic progenitors to adopt duodenal epithelial fates, establishing PTF1A as required for specification of pancreatic fate from undifferentiated foregut endoderm. Cre-mediated lineage tracing in vivo, Ptf1a null mouse analysis, transgene-based Pdx1 rescue experiments Nature genetics High 12185368
2004 Human PTF1A truncating mutations (705insG and C886T) cause pancreatic and cerebellar agenesis; reporter-gene studies with deletion mutants defined a C-terminal domain (beyond the bHLH domain) as crucial for PTF1A function. Positional cloning, reporter-gene transactivation assays with PTF1A deletion mutants, neuropathological analysis of Ptf1a-/- mice Nature genetics High 15543146
2004 Aortal endothelial cells specifically induce PTF1A expression in dorsal pancreatic endoderm to initiate dorsal pancreatic bud formation; tissue recombination experiments using Flk1-/- embryos lacking endothelial cells demonstrated this induction. Tissue recombination experiments, Flk1-/- mouse embryos lacking endothelial cells, in situ hybridization Development (Cambridge, England) High 14736742
2005 PTF1A is required in cerebellar ventricular zone progenitors to specify GABAergic neuronal fate; loss of Ptf1a (cerebelless mutant) causes failure of GABAergic neuron production; ectopic expression in glutamatergic neuron precursors in dorsal telencephalon converts them to GABAergic neurons with representative morphological and migratory features. Cerebelless mutant characterization, Cre-mediated lineage tracing, ectopic Ptf1a expression by electroporation Neuron High 16039563
2005 PTF1A is required in dorsal spinal cord progenitors for generation of GABAergic interneurons (dI4 and dILA populations marked by Lhx1/5 and Pax2); in Ptf1a null mice, dI4 neurons trans-fate to dI5 (Lmx1b+) and dILA to dILB (Lmx1b+;Tlx3+), establishing PTF1A as a determinant of GABAergic over glutamatergic neuronal fate. Ptf1a null mouse analysis, immunohistochemistry for interneuron markers, in situ hybridization Development (Cambridge, England) High 16291784
2006 PTF1A forms an active trimeric PTF1 complex with an E-protein (class I bHLH) and either RBPJ or RBPJL; HES family members (Hes1, Hey1, Hey2) directly interact with Ptf1a-p48 through co-immunoprecipitation and GST pulldown, inhibiting PTF1 transcriptional complex activity; the HES-Ptf1a interaction domain was mapped to the bHLH, Orange, and C-terminal domains of Hes1. Co-immunoprecipitation, yeast two-hybrid, GST pulldown assay, reporter gene transactivation assays The Biochemical journal High 16201968
2006 Ptf1a is expressed by post-mitotic retinal precursors and marks progenitors competent to exclusively produce horizontal and amacrine neurons; inactivation of Ptf1a causes fate-switch of these precursors to ganglion cell fate, resulting in complete loss of horizontal cells and decrease in amacrine cells; Ptf1a is a primary downstream target of the Foxn4 forkhead transcription factor. Cre-based lineage tracing, Ptf1a null mouse analysis, immunohistochemistry Development (Cambridge, England) High 17075007
2007 PTF1A occupies the conserved PTF1-binding site within area III of the Pdx1 promoter in E11.5 pancreatic buds; PTF1 specifically trans-activates area III-containing reporter expression, and the PTF1 site contributes to area III-dependent reporter gene expression in acinar AR42J cells. Chromatin immunoprecipitation (ChIP) from E11.5 pancreatic buds, reporter gene assays in cell lines, in vivo transgenic reporter analysis Molecular and cellular biology High 17403901
2007 PTF1A is required for differentiation of GABAergic and glycinergic amacrine cells and horizontal cells in mouse retina; Ptf1a-null retinas completely lack GABAergic and glycinergic amacrine cells and horizontal cells, with partial trans-differentiation of Ptf1a-expressing precursors to ganglion cells. Ptf1a conditional knockout in retina, lineage tracing, immunohistochemistry for cell-type-specific markers Development (Cambridge, England) High 17301087
2007 PTF1A is required for climbing fiber neuron development; Ptf1a-expressing progenitors in the dorsolateral caudal hindbrain generate climbing fiber neurons of the inferior olivary nucleus; in Ptf1a null mutants, putative CF neurons fail to migrate/differentiate, ION formation fails, and some cells fate-switch to mossy fiber neurons. Ptf1a-lacZ knock-in fate mapping, Ptf1a null mouse analysis, retrograde labeling, immunohistochemistry The Journal of neuroscience High 17928434
2008 PTF1A establishes a transcriptional autoregulatory loop via the trimeric PTF1 complex (PTF1A + E protein + RBPJ or RBPJL) binding to two conserved sites in the Ptf1a autoregulatory enhancer; the PTF1 complex also forms dual autoregulatory loops with the Rbpjl gene to maintain stable acinar cell phenotype. Transgenic reporter assays in mice, EMSA/binding site mutagenesis, ChIP from pancreatic tissue, cell line transfection Molecular and cellular biology High 18606784
2008 PTF1A acts as a master regulator of glycinergic, peptidergic, and GABAergic transmitter phenotypes in dorsal spinal cord inhibitory neurons; Pax2 is a downstream target of Ptf1a; Ptf1a is required for expression of GlyT2, NPY, N/OFQ, SOM, ENK, DYN, and GAL. Ptf1a null mouse analysis, in situ hybridization, immunohistochemistry Developmental biology High 18634777
2008 Nkx6.1/Nkx6.2 and PTF1A function as cross-repressive lineage determinants in multipotent pancreatic progenitors; PTF1A is required and sufficient to repress the endocrine lineage program and specify progenitors toward acinar fate, operating only during a critical competence window. Genetic loss-of-function and gain-of-function mouse models, lineage tracing Developmental cell High 20627083
2009 The PTF1-J trimeric complex (PTF1A + E protein + RBPJ) directly regulates Neurog2 expression in the dorsal neural tube through a 3' enhancer containing a required PTF1-J binding site; Ptf1a occupies the Neurog2 enhancer in vivo (ChIP from neural tube tissue), and Neurog2 is the first identified neural target of PTF1A. ChIP from neural tube tissue, gain/loss of Ptf1a function in vivo (chick and mouse), reporter assays with site mutagenesis Development (Cambridge, England) High 19641016
2009 PTF1A directly binds to PTF-binding motifs in the 5'-flanking regions of Nephrin and Neph3 genes and activates their transcription; expression of Nephrin and Neph3 is lost in Ptf1a-null mice and induced by forced PTF1A expression, establishing them as direct downstream targets in neural development. ChIP (direct binding to endogenous loci), reporter gene activation assays, Ptf1a null mouse analysis, gain-of-function The Journal of biological chemistry High 19887377
2009 PTF1A-mediated autoregulation in the nervous system requires PTF1-J complex binding to a conserved 5' 2.3 kb autoregulatory element; a separate Ptf1a-independent 12.4 kb 3' regulatory region initiates Ptf1a expression independently of PTF1A, establishing two distinct transcriptional mechanisms controlling Ptf1a levels. Transgenic reporter assays in mice, in vitro binding assays (PTF1-J complex), Ptf1a null mouse analysis The Journal of neuroscience High 19741120
2009 The histone acetyltransferase p/CAF interacts with PTF1A (p48) in acinar cells in vivo, is associated with PTF1 target gene promoters, and acetylates PTF1A at Lys200; the K200R mutation abolishes PTF1A transcriptional activity and cooperation with RBP-L, establishing that p/CAF-mediated acetylation is required for full PTF1 transcriptional activity. Co-immunoprecipitation from acinar cells, ChIP at PTF1 target promoters, site-directed mutagenesis (K200R), reporter gene assays The Biochemical journal High 18834332
2010 Id3 directly interacts with PTF1A (p48) and E47, disrupting E47/PTF1A interaction; gastrin-induced increases in Id3 expression cause cytoplasmic mislocalization of PTF1A in acinar cells; Id3 silencing reverses the gastrin-induced cytoplasmic mislocalization, establishing E47-dependent nuclear import as the mechanism governing PTF1A nuclear localization. Co-immunoprecipitation, Id3 siRNA knockdown, subcellular localization imaging in AR4-2J acinar cells International journal of cancer Medium 20830706
2011 PTF1A activates Dll1 expression in multipotent pancreatic progenitor cells, which maintains Hes1 expression and in turn sustains Ptf1a protein levels, forming a Ptf1a-Dll1-Hes1-Ptf1a feedback circuit that promotes MPC proliferation and pancreatic growth; this represents an alternative to classical lateral inhibition. Genetic mouse mutants (Dll1, Hes1, Ptf1a), epistasis analysis, Neurog3 conditional deletion, BrdU proliferation assay Development (Cambridge, England) High 22096075
2011 In zebrafish, postembryonic antagonism of Ptf1a induces expression of endocrine genes including insulin in exocrine compartment; lineage tracing demonstrates induced insulin+ cells derive from acinar cells, establishing that continuous PTF1A activity is required to maintain acinar cell identity and suppress endocrine fate. Genetic lineage tracing, postembryonic Ptf1a antagonism, immunohistochemistry Current biology Medium 21497092
2012 PTF1A directly regulates Mnx1 (via a distant enhancer), Pdx1, Nkx6.1, and Onecut1 in pancreatic progenitors; ChIP-seq identified PTF1A-bound genomic regions near genes required for pancreas bud maintenance, establishing PTF1A as a direct upstream activator of a transcription factor network for pancreatic progenitor maintenance. RNA profiling, ChIP-sequencing from pancreatic progenitors, reporter gene assays Molecular and cellular biology High 22232429
2012 Rbms3 RNA-binding protein binds to the 3'UTR of Ptf1a mRNA (but not Pdx1 3'UTR) and stimulates Ptf1a translation; knockdown of Rbms3 in AR42J-B13 cells reduces PTF1A expression, establishing post-transcriptional regulation of PTF1A by Rbms3. RNA pull-down/binding assay, ectopic expression of reporter with Ptf1a 3'UTR, siRNA knockdown in pancreatic cell line DNA and cell biology Medium 22372950
2013 Prdm13 is a direct transcriptional target of the PTF1A-RBPJ complex in the dorsal neural tube; Prdm13 suppresses glutamatergic (Tlx3+) and promotes GABAergic (Pax2+) neuronal fate by blocking Neurog2-mediated Tlx3 activation; Prdm13 also exerts negative autoregulation. Ptf1a gain/loss-of-function in Xenopus and mice, morpholino knockdown, chick neural tube electroporation, RBPJ complex requirement tested Developmental biology High 24370451
2013 Most PTF1A-bound genomic regions are tissue-specific (pancreas vs. neural tube) and coincide with open chromatin regions; Foxa2 colocalizes with PTF1A in embryonic pancreatic chromatin and acts synergistically with PTF1A in cell transfection assays, establishing lineage-specific chromatin landscape as a constraint on PTF1A binding specificity. In vivo ChIP-seq from developing pancreas and neural tube, transgenic reporter assays, co-transfection synergy assays, ATAC-seq equivalent open chromatin analysis Molecular and cellular biology High 23754747
2013 ICAT (inhibitor of β-catenin and Tcf4) is a novel PTF1A interactor identified by yeast two-hybrid; ICAT overexpression negatively regulates PTF1 activity by direct binding to PTF1A, displacing p/CAF, reducing PTF1A-RBPJl interaction, and impairing PTF1A acetylation, independently of β-catenin. Yeast two-hybrid screen, in vitro and in vivo co-immunoprecipitation, reporter gene assays, co-immunoprecipitation mapping of interaction The Biochemical journal High 23339455
2013 A retrotransposon (ETn) insertion 12.5 kb upstream of Ptf1a significantly upregulates Ptf1a expression in Danforth's short tail (Sd) mutant embryos at E9.5, and ectopic PTF1A misexpression in the notochord, hindgut, cloaca, and mesonephros causes the Sd phenotype via attenuation of Cdx2 and downstream targets T, Wnt3a, and Cyp26a1. Next-generation sequencing, Sanger sequencing, knockout and knock-in mouse models, in situ hybridization PLoS genetics High 23436999 23437000
2013 PTF1A enhancer mutations in a ~400-bp sequence 25 kb downstream of PTF1A abolish enhancer activity in reporter gene assays; these mutations are the most common cause of isolated pancreatic agenesis. Whole-genome sequencing, epigenomic annotation in hESC-derived pancreatic progenitors, reporter gene/enhancer activity assays Nature genetics High 24212882
2014 In Ptf1a null mice, cerebellar ventricular zone cells initiate more ventral brainstem expression programs (including Lmx1b and Tlx3), exit the cerebellar anlage, and contribute to adjacent brainstem or die, establishing PTF1A as required to segregate cerebellar from ventral brainstem fates. Genetic fate mapping in Ptf1a-/- mice, birthdating, gene expression analysis (immunohistochemistry, in situ hybridization) Proceedings of the National Academy of Sciences High 24733890
2014 Ectopic expression of Ptf1a in glutamatergic neuron precursors in the cerebellar rhombic lip converts them to produce GABAergic populations (Purkinje cells and GABAergic interneurons); Ptf1a and Atoh1 mutually negatively regulate each other's expression, establishing PTF1A as both necessary and sufficient for GABAergic specification in cerebellar neuroepithelium. Knock-in mouse lines (Ptf1a-Atoh1 and Atoh1-Ptf1a), in utero electroporation, BrdU birthdating The Journal of neuroscience High 24695699
2015 PTF1A expression is lost in mouse and human pancreatic intraepithelial neoplasia (PanIN); PTF1A loss alone is sufficient to induce acinar-to-ductal metaplasia and a KRAS-permissive gene expression profile; Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, establishing PTF1A as a tumor suppressor in pancreas. Conditional Ptf1a knockout in mice, histological analysis, gene expression profiling (RNA-seq), KRAS combination mouse models eLife High 26151762
2015 Tfap2a and Tfap2b are major downstream effectors of PTF1A in retinal amacrine cell differentiation; their expression is dramatically downregulated in Ptf1a null retina; overexpression promotes glycinergic and GABAergic amacrine cell differentiation, while simultaneous knockdown has opposite effects, establishing a Foxn4/RORβ1-Ptf1a-Tfap2a/2b regulatory cascade. RNA-seq, immunolabeling in Ptf1a null retina, overexpression and knockdown experiments in mouse retinas Molecular brain High 25966682
2015 PTF1a-Rbpj/Ptf1a complex drives Dll1 expression in multipotent pancreatic progenitors via direct Ptf1a-mediated transcriptional control; Hes1 is required to sustain Ptf1a expression levels in early MPCs. Already captured in PMID 22096075; see above Development (Cambridge, England) Medium 22096075
2016 PTF1A directly maintains expression of genes for secretory digestive enzyme production, UPR surveillance, and a ten-member transcription factor network in adult acinar cells; PTF1A depletion causes UPR imbalance, cellular injury, acinar metaplasia, and derepression of stomach-characteristic genes, establishing PTF1A as a direct transcriptional maintainer of acinar cell identity. RNA-seq and ChIP-seq from adult pancreas after Ptf1a conditional depletion in vivo Molecular and cellular biology High 27697859
2016 A highly conserved distal 3' enhancer (10.8 kb downstream of Ptf1a) drives expression in dorsal neural tube progenitors; Paired homeodomain binding motifs are required for activator function and zinc finger motifs for repressor function; PAX6 and SOX3 can increase enhancer activity in reporter assays. Transgenic reporter assays in chick and mouse, site-directed mutagenesis of binding motifs, transfection reporter assays Developmental biology Medium 27350561
2018 PTF1A alone is sufficient to directly reprogram mouse and human fibroblasts into self-renewable induced neural stem cells; this reprogramming depends on PTF1A's Notch-independent interaction with Rbpj, which leads to activation of TF genes and Notch signaling required for NSC specification and self-renewal. Direct reprogramming of fibroblasts, Co-IP for PTF1A-Rbpj interaction, transcriptome analysis, transplantation into AD mouse models Nature communications High 30030434
2018 Homozygous deletion of Ptf1a in adult acinar cells causes severe apoptosis mediated through endoplasmic reticulum stress via the ATF6 and PERK (but not IRE1) UPR pathways, with CHOP upregulation as the pro-apoptotic signal. Elastase-CreERTM; Ptf1a-floxed/floxed conditional KO, electron microscopy, western blot for UPR pathway components Scientific reports Medium 30361559
2018 Ptf1a is expressed in neuroepithelial cells and immature neurons around the third ventricle giving rise to hypothalamic neurons; conditional Ptf1a deficiency causes abnormal sex-biased behaviors, and Kiss1 expression is drastically reduced in the cKO hypothalamus, establishing PTF1A as a regulator of hypothalamic sexual differentiation. Conditional Ptf1a knockout, behavioral testing, gonadal hormone administration to gonadectomized mice, gene expression analysis Cell reports Medium 29972793
2020 Positive transcriptional autoregulatory feedback through the PTF1A autoregulatory enhancer is required to attain PTF1A levels necessary for specifying Pdyn+ and Gal+ inhibitory dorsal spinal cord interneurons; mutations in the autoregulatory enhancer reduce PTF1A levels and cause a severe itch phenotype with increased sensitivity to itch but unaffected acute pain sensitivity. Targeted mutations in Ptf1a cis-regulatory elements in mice, quantitative analysis of neuronal populations, behavioral testing (itch, mechanical, thermal pain) Genes & development High 32241803
2020 A spinal subpopulation of Ptf1a-derived inhibitory neurons gates mechanosensory information self-generated during movement; these neurons receive tactile and motor input and establish presynaptic inhibitory contacts on mechanosensory afferents; loss of Ptf1a neurons leads to increased hairy skin sensitivity and chronic itch partially mediated by GRPR spinal neurons. Conditional Ptf1a neuron ablation/inactivation, anatomical tracing, chemogenetic activation (DREADD), behavioral testing Cell reports High 33238109
2024 During PTF1A-mediated fibroblast-to-NSC transdifferentiation, PTF1A binds to subTAD boundaries associated with elevated CTCF binding and enhanced boundary insulation, reorganizes chromatin loops, activates enhancers and super-enhancers near low-insulation boundaries, and modulates H3K27ac deposition to drive gene expression changes. Hi-C, ChIP-seq (PTF1A, CTCF, H3K27ac), RNA-seq multiomics integration Communications biology Medium 39537822

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nature genetics 808 12185368
1998 The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes & development 417 9851981
2005 Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron 390 16039563
2004 Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nature genetics 312 15543146
2013 Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development (Cambridge, England) 240 23325761
2010 Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Developmental cell 223 20627083
2013 Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nature genetics 211 24212882
2006 Ptf1a determines horizontal and amacrine cell fates during mouse retinal development. Development (Cambridge, England) 199 17075007
2004 Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development (Cambridge, England) 195 14736742
2005 Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn. Development (Cambridge, England) 183 16291784
2007 Ptf1a is essential for the differentiation of GABAergic and glycinergic amacrine cells and horizontal cells in the mouse retina. Development (Cambridge, England) 169 17301087
2008 Pdx-1 and Ptf1a concurrently determine fate specification of pancreatic multipotent progenitor cells. Developmental biology 151 18294628
2015 The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. eLife 131 26151762
2007 Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression. Proceedings of the National Academy of Sciences of the United States of America 129 17360405
2004 Evolutionary conserved role of ptf1a in the specification of exocrine pancreatic fates. Developmental biology 91 15031114
2006 Combined ectopic expression of Pdx1 and Ptf1a/p48 results in the stable conversion of posterior endoderm into endocrine and exocrine pancreatic tissue. Genes & development 83 16751182
2008 Ptf1a, Lbx1 and Pax2 coordinate glycinergic and peptidergic transmitter phenotypes in dorsal spinal inhibitory neurons. Developmental biology 82 18634777
2008 Transcriptional autoregulation controls pancreatic Ptf1a expression during development and adulthood. Molecular and cellular biology 80 18606784
2007 Origin of climbing fiber neurons and their developmental dependence on Ptf1a. The Journal of neuroscience : the official journal of the Society for Neuroscience 79 17928434
2014 Specification of spatial identities of cerebellar neuron progenitors by ptf1a and atoh1 for proper production of GABAergic and glutamatergic neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 73 24695699
2009 Ptf1a is expressed transiently in all types of amacrine cells in the embryonic zebrafish retina. Neural development 73 19732413
2018 Direct reprogramming of fibroblasts into neural stem cells by single non-neural progenitor transcription factor Ptf1a. Nature communications 72 30030434
2008 Graded levels of Ptf1a differentially regulate endocrine and exocrine fates in the developing pancreas. Genes & development 72 18519637
2007 Ptf1a binds to and activates area III, a highly conserved region of the Pdx1 promoter that mediates early pancreas-wide Pdx1 expression. Molecular and cellular biology 70 17403901
2016 Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A. Molecular and cellular biology 65 27697859
2004 Differential requirement for ptf1a in endocrine and exocrine lineages of developing zebrafish pancreas. Developmental biology 63 15183727
2004 Differential requirement for ptf1a in endocrine and exocrine lineages of developing zebrafish pancreas. Developmental biology 62 15570689
2007 Ptf1a triggers GABAergic neuronal cell fates in the retina. BMC developmental biology 59 17910758
2015 Tfap2a and 2b act downstream of Ptf1a to promote amacrine cell differentiation during retinogenesis. Molecular brain 58 25966682
2008 Reduction of Ptf1a gene dosage causes pancreatic hypoplasia and diabetes in mice. Diabetes 58 18591390
2011 Ptf1a-mediated control of Dll1 reveals an alternative to the lateral inhibition mechanism. Development (Cambridge, England) 55 22096075
2008 Generation and characterization of Ptf1a antiserum and localization of Ptf1a in relation to Nkx6.1 and Pdx1 during the earliest stages of mouse pancreas development. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 51 18347078
2011 Suppression of Ptf1a activity induces acinar-to-endocrine conversion. Current biology : CB 48 21497092
2009 Neurog2 is a direct downstream target of the Ptf1a-Rbpj transcription complex in dorsal spinal cord. Development (Cambridge, England) 48 19641016
2007 Differential ability of Ptf1a and Ptf1a-VP16 to convert stomach, duodenum and liver to pancreas. Developmental biology 46 17320068
2012 RNA profiling and chromatin immunoprecipitation-sequencing reveal that PTF1a stabilizes pancreas progenitor identity via the control of MNX1/HLXB9 and a network of other transcription factors. Molecular and cellular biology 45 22232429
2018 Transcription factor Ptf1a in development, diseases and reprogramming. Cellular and molecular life sciences : CMLS 42 30470852
2014 Transformation of the cerebellum into more ventral brainstem fates causes cerebellar agenesis in the absence of Ptf1a function. Proceedings of the National Academy of Sciences of the United States of America 42 24733890
2013 The Prdm13 histone methyltransferase encoding gene is a Ptf1a-Rbpj downstream target that suppresses glutamatergic and promotes GABAergic neuronal fate in the dorsal neural tube. Developmental biology 42 24370451
2013 Genome-wide expression analysis of Ptf1a- and Ascl1-deficient mice reveals new markers for distinct dorsal horn interneuron populations contributing to nociceptive reflex plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 23616538
2008 Exdpf is a key regulator of exocrine pancreas development controlled by retinoic acid and ptf1a in zebrafish. PLoS biology 40 19067490
2009 Multiple transcriptional mechanisms control Ptf1a levels during neural development including autoregulation by the PTF1-J complex. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 19741120
2016 Loss of Ptf1a Leads to a Widespread Cell-Fate Misspecification in the Brainstem, Affecting the Development of Somatosensory and Viscerosensory Nuclei. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 26937009
2013 Program specificity for Ptf1a in pancreas versus neural tube development correlates with distinct collaborating cofactors and chromatin accessibility. Molecular and cellular biology 32 23754747
2012 Tlx1/3 and Ptf1a control the expression of distinct sets of transmitter and peptide receptor genes in the developing dorsal spinal cord. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 22723691
2011 Ptf1a/Rbpj complex inhibits ganglion cell fate and drives the specification of all horizontal cell subtypes in the chick retina. Developmental biology 30 21839069
2009 A Turkish newborn infant with cerebellar agenesis/neonatal diabetes mellitus and PTF1A mutation. Genetic counseling (Geneva, Switzerland) 27 19650412
2007 Temporal and spatial expression of transcription factors FoxN4, Ptf1a, Prox1, Isl1 and Lim1 mRNA in the developing chick retina. Gene expression patterns : GEP 26 18006384
2006 Interactions between hairy/enhancer of split-related proteins and the pancreatic transcription factor Ptf1-p48 modulate function of the PTF1 transcriptional complex. The Biochemical journal 26 16201968
2009 Ptf1a directly controls expression of immunoglobulin superfamily molecules Nephrin and Neph3 in the developing central nervous system. The Journal of biological chemistry 25 19887377
2019 SOX9+/PTF1A+ Cells Define the Tip Progenitor Cells of the Human Fetal Pancreas of the Second Trimester. Stem cells translational medicine 21 31631582
2017 Pancreatic Agenesis due to Compound Heterozygosity for a Novel Enhancer and Truncating Mutation in the PTF1A Gene. Journal of clinical research in pediatric endocrinology 21 28663161
2017 Prdm13 forms a feedback loop with Ptf1a and is required for glycinergic amacrine cell genesis in the Xenopus Retina. Neural development 21 28863786
2015 Fate mapping of ptf1a-expressing cells during pancreatic organogenesis and regeneration in zebrafish. Developmental dynamics : an official publication of the American Association of Anatomists 21 25773748
2012 Rbms3, an RNA-binding protein, mediates the expression of Ptf1a by binding to its 3'UTR during mouse pancreas development. DNA and cell biology 21 22372950
2018 Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain. Cell reports 20 29972793
2018 Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway. Scientific reports 19 30361559
2013 Next-generation sequencing identifies the Danforth's short tail mouse mutation as a retrotransposon insertion affecting Ptf1a expression. PLoS genetics 19 23437000
2018 Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment. Molecular oncology 18 29719936
2014 Dominant and context-specific control of endodermal organ allocation by Ptf1a. Development (Cambridge, England) 17 25371369
2017 Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation. Journal of clinical research in pediatric endocrinology 16 28943513
2016 Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation. Diabetes 16 27284104
2013 Ectopic expression of Ptf1a induces spinal defects, urogenital defects, and anorectal malformations in Danforth's short tail mice. PLoS genetics 15 23436999
2020 Spinal Inhibitory Ptf1a-Derived Neurons Prevent Self-Generated Itch. Cell reports 14 33238109
2015 Variable Phenotype of Diabetes Mellitus in Siblings with a Homozygous PTF1A Enhancer Mutation. Hormone research in paediatrics 14 26184423
2014 Ectopic Ptf1a expression in murine ESCs potentiates endocrine differentiation and models pancreas development in vitro. Stem cells (Dayton, Ohio) 12 24375815
2014 Ascl1 as a novel player in the Ptf1a transcriptional network for GABAergic cell specification in the retina. PloS one 12 24643195
2009 p/CAF modulates the activity of the transcription factor p48/Ptf1a involved in pancreatic acinar differentiation. The Biochemical journal 12 18834332
2020 Gsx2 is required for specification of neurons in the inferior olivary nuclei from Ptf1a-expressing neural progenitors in zebrafish. Development (Cambridge, England) 11 32928905
2017 LSL-KrasG12D; LSL-Trp53R172H/+; Ink4flox/+; Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer. PloS one 11 28475592
2013 Distinct enhancers of ptf1a mediate specification and expansion of ventral pancreas in zebrafish. Developmental biology 11 23876428
2010 Id3 modulates cellular localization of bHLH Ptf1-p48 protein. International journal of cancer 11 20830706
2023 Ptf1a expression is necessary for correct targeting of spiral ganglion neurons within the cochlear nuclei. Neuroscience letters 10 37055006
2020 Positive autofeedback regulation of Ptf1a transcription generates the levels of PTF1A required to generate itch circuit neurons. Genes & development 10 32241803
2020 Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations. The Journal of clinical endocrinology and metabolism 10 32893856
2012 MiR-18a regulates expression of the pancreatic transcription factor Ptf1a in pancreatic progenitor and acinar cells. FEBS letters 10 22265691
2021 Engineering of a functional pancreatic acinus with reprogrammed cancer cells by induced PTF1a expression. Lab on a chip 9 34581719
2017 ptf1a , ela3l cells are developmentally maintained progenitors for exocrine regeneration following extreme loss of acinar cells in zebrafish larvae. Disease models & mechanisms 9 28138096
2017 Conventional insulin pump therapy in two neonatal diabetes patients harboring the homozygous PTF1A enhancer mutation: Need for a novel approach for the management of neonatal diabetes. The Turkish journal of pediatrics 7 29624227
2015 Misexpression of ptf1a in cortical pyramidal cells in vivo promotes an inhibitory peptidergic identity. The Journal of neuroscience : the official journal of the Society for Neuroscience 7 25878276
2016 Regulating the dorsal neural tube expression of Ptf1a through a distal 3' enhancer. Developmental biology 6 27350561
2013 ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours. The Biochemical journal 6 23339455
2024 Foxp and Skor family proteins control differentiation of Purkinje cells from Ptf1a- and Neurog1-expressing progenitors in zebrafish. Development (Cambridge, England) 5 38456494
2017 Mechanistic insights into the activity of Ptf1-p48 (pancreas transcription factor 1a): probing the interactions levels of Ptf1-p48 with E2A-E47 (transcription factor E2-alpha) and ID3 (inhibitor of DNA binding 3). Journal of biomolecular structure & dynamics 3 28571517
2015 Mutations in PTF1A are not a common cause for human VATER/VACTERL association or neural tube defects mirroring Danforth's short tail mouse. Molecular medicine reports 3 25775927
2024 Multiscale 3D genome rewiring during PTF1A-mediated somatic cell reprogramming into neural stem cells. Communications biology 2 39537822
2023 Isolated Pancreatic Agenesis Secondary to PTF1A Gene Mutation: A Case Series and Literature Review. Cureus 2 37854477
2023 Expression and clinicopathological characteristics of PDX1, PTF1A, and SALL4 in large and small ducts of ectopic pancreas located in gastro-duodenum and jejunum. Heliyon 1 37519669
2022 Ptf1a Promoter-Driven Cre Expression During Spermatogenesis Causes Germline Recombination. Pancreas 1 35195600
2016 PTF1a Activity in Enriched Posterior Foregut Endoderm, but Not Definitive Endoderm, Leads to Enhanced Pancreatic Differentiation in an In Vitro Mouse ESC-Based Model. Stem cells international 1 27066080
2026 Compound Heterozygosity of PTF1A Exonic and Enhancer Variants in a Japanese Boy With Pancreatic Hypoplasia. Clinical genetics 0 41536248
2025 A Rare PTF1A Enhancer Mutation Causing Neonatal Diabetes Mellitus with Pancreatic Agenesis: Case Report and Considerations for Genetic Evaluation. International journal of endocrinology and metabolism 0 40443916

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