| 1998 |
bmp2b (zebrafish ortholog of BMP4/BMP2B) functions cell-nonautonomously as a BMP ligand to specify ventral cell fates along the dorsoventral axis; swirl mutant (bmp2b loss-of-function) phenotypes are rescued by overexpression of bmp4, bmp2b, an activated BMP type I receptor, or Smad1, placing bmp2b upstream of receptor and Smad1 in a linear pathway. |
Genetic epistasis, chromosomal mapping, cDNA sequence analysis, mRNA rescue injections in zebrafish |
Developmental biology |
High |
9676195
|
| 1998 |
BMP4 is required for lens induction from the optic vesicle in the mouse embryo; exogenous BMP4 protein applied to explants rescues lens induction (including ectodermal Sox2 expression) in Bmp4 null mutants, while BMP4-soaked beads alone are insufficient, indicating BMP4 acts as one component of multiple optic vesicle signals. BMP4 regulates downstream expression of Msx2 in the optic vesicle and acts independently of Pax6. |
Homozygous null mouse mutant analysis, explant culture rescue with exogenous BMP4 protein and BMP4-carrying beads, in situ hybridization for Sox2 and Msx2 |
Genes & development |
High |
9851982
|
| 1999 |
Wnt8/beta-catenin signaling represses Bmp4 transcription in the dorsal ectoderm of Xenopus embryos at early gastrula stages, contributing to neural induction; this repression requires TCF transcription factor activity but is independent of the BMP antagonist Noggin. |
mRNA overexpression of Wnt8, Xwnt8, beta-catenin, dominant-negative GSK3, truncated TCF in Xenopus embryos; in situ hybridization for Bmp4 and neural markers |
Genes & development |
Medium |
10601040
|
| 1999 |
Zebrafish Smad5 (somitabun) acts downstream of Bmp2b signaling to mediate Bmp2b autoregulation during dorsoventral patterning; an antimorphic Smad5 mutation strongly dorsalizes embryos similarly to bmp2b loss-of-function, and double-mutant and rescue experiments place sbn (smad5) genetically downstream of bmp2b. |
Zebrafish genetic mutant analysis, double-mutant epistasis, temporally controlled mRNA rescue injections, chimera analyses, marker gene expression |
Development (Cambridge, England) |
High |
10207140
|
| 2000 |
Bmp2b and Bmp7 do not function redundantly in zebrafish dorsoventral patterning (double null mutants show no additive phenotype), but overexpression experiments reveal that Bmp2b and Bmp7 synergize in ventralization through a cell-autonomous mechanism, suggesting they act as heterodimers in vivo. |
Zebrafish mutant analysis, double mutant construction, mRNA overexpression synergy assays, zebrafish bmp7 gene isolation and chromosomal synteny |
Development (Cambridge, England) |
High |
10662635
|
| 1997 |
Bmp4 gene dosage is essential for normal development; heterozygous Bmp4 null mice show haploinsufficient phenotypes (cystic kidney, craniofacial malformations, microphthalmia, polydactyly). Genetic interactions with Gli3(XtJ) and Alx4(tm1) mutations enhance the polydactylous phenotype, indicating BMP4 participates in a multigenic pathway controlling anterior digit patterning. |
Mouse null mutant and heterozygote analysis on C57BL/6 background, double heterozygous crosses with Gli3 and Alx4 mutations, phenotypic characterization |
Developmental biology |
High |
9268572
|
| 2001 |
BMP4 mediates programmed cell death in the developing chick dorsal optic cup; local addition of BMP4 induces, and Noggin (BMP4 antagonist) suppresses, apoptosis in optic vesicle cultures and in ovo. BMP4 also increases cell proliferation in retina cultures. Bmp4 is coexpressed with downstream apoptosis mediators Msx1 and Msx2 and with BMP pathway components (BmprIA, BmprII, Smad1) in dorsal retina. |
In situ hybridization, in ovo BMP4/Noggin bead implantation, optic vesicle explant cultures with BMP4 and Noggin, TUNEL assay, BrdU proliferation assay |
The Journal of neuroscience |
High |
11160400
|
| 1997 |
BMP4 induces programmed cell death via Msx2-mediated pathway; BMP4 treatment of P19 cells induces Msx2 transcription and cell death upon aggregation, and ectopic Msx2 expression increases apoptosis. BMP4 does not further increase apoptosis in Msx2-overexpressing cells, placing Msx2 downstream of BMP4 in the apoptosis pathway. |
P19 cell aggregation assays, ectopic Msx2 overexpression, BMP4 treatment, TUNEL assay for apoptosis, gene expression analysis |
Developmental biology |
High |
9205134
|
| 2003 |
The homeodomain transcriptional repressor Bozozok/Dharma (encoded by bozozok) directly represses bmp2b transcription by binding to two high-affinity binding sites within the first intron of the bmp2b gene, establishing the earliest transcriptional asymmetry of bmp2b expression in the zebrafish blastula. An En-Boz (repressor) fusion rescues the boz phenotype while VP16-Boz acts as an antimorph, demonstrating Boz functions as a transcriptional repressor. |
mRNA overexpression of Boz-fusion proteins (En-Boz, VP16-Boz), cycloheximide treatment to distinguish direct vs. indirect effects, identification of Boz-binding sites in bmp2b intron 1, deletion of control elements in reporter assays |
Development (Cambridge, England) |
High |
12835381
|
| 1999 |
The nieuwkoid/dharma homeobox transcription factor represses bmp2b expression on the dorsal side of the zebrafish pregastrula; loss-of-function (boz mutants) leads to derepression of zbmp2b on the dorsal side, and ectopic expression of nieuwkoid/dharma is sufficient to downregulate zbmp2b expression. |
Zebrafish mutant analysis, mRNA overexpression, in situ hybridization for zbmp2b |
Developmental biology |
Medium |
10545230
|
| 2001 |
Bmp2b and Oep regulate gata5 expression in myocardial precursors, and Gata5 acts downstream of both signals to regulate nkx2.5 expression and promote myocardial differentiation in zebrafish; forced expression of gata5 in bmp2b and oep mutants restores nkx2.5 and cmlc1 expression, placing gata5 downstream of bmp2b in the myocardial differentiation pathway. |
Zebrafish mutant analysis (swirl/bmp2b, Zoep), mRNA overexpression of gata5, in situ hybridization for nkx2.5, gata5, cmlc1 |
Developmental biology |
High |
11397003
|
| 2006 |
BMP4 activation and secretion are negatively regulated by an intracellular interaction with the BMP antagonist Gremlin; Gremlin interacts with the BMP4 precursor intracellularly, preventing secretion of mature BMP4. A 30-amino acid peptide within the Gremlin DAN domain is essential for BMP4 interaction. |
Co-immunoprecipitation, secretion assay (measuring mature BMP4 in conditioned medium), domain-deletion mutagenesis identifying critical 30-aa peptide in Gremlin DAN domain |
The Journal of biological chemistry |
High |
16880207
|
| 2009 |
RANKL increases vascular smooth muscle cell calcification through RANK receptor activation, which stimulates the alternative NF-κB pathway (via IKKα) to upregulate BMP4 expression; BMP4 then mediates the calcification response, as demonstrated by Noggin blockade abolishing RANKL-induced calcification and by shRNA knockdown of RANK preventing BMP4 upregulation. |
shRNA knockdown of RANK, IKKα inhibition, Noggin treatment, calcification assay, in vivo vascular calcium measurement with colocalization of RANKL and BMP4 |
Circulation research |
High |
19325147
|
| 2015 |
The BMP4 prodomain is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity; BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo, and the BMP4 prodomain enables homodimers to signal in contexts where they normally lack activity. |
In vivo coexpression of BMP4 and BMP7 precursors, prodomain swap experiments, bioactivity assays in zebrafish embryo developmental rescue system |
Proceedings of the National Academy of Sciences of the United States of America |
High |
25902523
|
| 2020 |
NGLY1-mediated deglycosylation of misfolded BMP4 in the ER is required for its retrotranslocation and proteasomal degradation during ERAD; accumulation of misfolded BMP4 in the ER causes ER stress and recruits NGLY1 to the ER, where it deglycosylates misfolded BMP4 to permit retrotranslocation, allowing properly-folded BMP4 to proceed through the secretory pathway and signal. |
Drosophila Dpp and mouse BMP4 genetic and biochemical experiments, ER stress assays, ERAD pathway analysis, in vivo signaling readouts |
eLife |
High |
32720893
|
| 2003 |
BMP4 acts upstream of FGF7/FGF10 in regulation of early T-cell development; BMP4 acts primarily through thymic stroma to upregulate Foxn1 and stroma-expressed chemokines, and BMP effects on thymocyte development can be suppressed by FGF receptor antagonist, establishing BMP4→stroma→FGF pathway order. |
Thymic organ culture with BMP4 and FGF7/FGF10, FGF receptor antagonist cotreatment, gene expression analysis of Foxn1 and chemokines |
Blood |
Medium |
12920023
|
| 2006 |
BMP4 regulates pancreatic progenitor cell expansion through induction of Id2 expression; BMP4 stimulation promotes Id2 binding to the bHLH transcription factor NeuroD, thereby blocking endocrine progenitor differentiation and instead promoting progenitor expansion. Neutralization of BMP4 in a mouse islet regeneration model reduces duct epithelial cell expansion. |
AR42J cell culture BMP4 stimulation, Id2-NeuroD co-immunoprecipitation, BMP4 neutralization in mouse islet regeneration model, gene expression analysis |
The Journal of biological chemistry |
Medium |
16547003
|
| 2009 |
BMP4 deficiency causes a microenvironmental defect in the hematopoietic stem cell niche, reducing HSC number and repopulating activity; BMP4 is expressed in osteoblasts, endothelial cells, and megakaryocytes, and BMP4-deficient recipients show reduced engraftment and function of wild-type HSCs in serial transplantation and parabiosis models. |
BMP4 hypomorph mouse model, reporter gene expression, serial transplantation, parabiosis, competitive repopulation assay, flow cytometry for HSC markers |
Blood |
High |
19759357
|
| 2010 |
Agrin N-terminal follistatin domains bind BMP4 (and BMP2, TGFβ1) with relatively high affinity (Kd ~10−8–10−7 M as measured by surface plasmon resonance) and inhibit BMP4 activity in reporter assays with half-maximal inhibition at ~5×10−7 M. |
Surface plasmon resonance spectroscopy for binding affinity measurement, reporter assays for BMP4 activity inhibition |
PloS one |
High |
20505824
|
| 2014 |
BMP4 and BMP7 downregulate pentraxin 3 (PTX3) expression in human granulosa cells via Smad-dependent signaling; BMP4 uses ALK3/ALK6 receptors to phosphorylate Smad1/5/8, which (with Smad4) suppresses PTX3 transcription. Knockdown of ALK3/ALK6 or Smad4 reverses BMP4-mediated PTX3 suppression. |
siRNA knockdown of ALK2, ALK3, ALK6, Smad4; BMP type I receptor inhibitors (dorsomorphin, DMH-1); Western blot for phospho-Smad1/5/8; quantitative RT-PCR; ELISA |
The Journal of clinical endocrinology and metabolism |
High |
25514099
|
| 2014 |
Fam20C kinase phosphorylates BMP4 to promote its secretion; mutation of the BMP4 phosphorylation site elevates lysosomal degradation of BMP4 and reduces its secretion from breast cancer cells. Fam20C-dependent phosphorylation of BMP4 facilitates osteoclastogenesis and bone metastasis. |
BMP4 phosphorylation site mutagenesis, BMP4 secretion assays, lysosomal degradation assay, osteoclastogenesis assay, in vivo bone metastasis model |
Cancer research |
Medium |
34433585
|
| 2019 |
BMP4, by interacting with the BMPRI-II heterocomplex, induces c-Src phosphorylation which in turn transactivates VEGFR2, leading to an angiogenic response; BMP4 does not directly bind VEGFR2. BMPR inhibitor dorsomorphin prevents c-Src activation, and c-Src inhibition reduces downstream VEGFR2 phosphorylation and angiogenesis in a chick CAM assay. |
VEGFR2 phosphorylation assay, c-Src phosphorylation assay, BMPR inhibitor dorsomorphin, c-Src specific inhibitor, chick embryo chorioallantoic membrane angiogenesis assay, BMP4/VEGFR2 interaction test |
Angiogenesis |
Medium |
31363885
|
| 2015 |
BMP4 promotes commitment of mesenchymal/adipose-derived stem cell precursors and drives beige/brown adipogenesis; BMP4-induced transcriptional activation of PPARγ promotes beige/brown phenotype. Gremlin-1 (GREM1), secreted by (pre)adipocytes, antagonizes BMP4 and causes BMP4 resistance in precursors in hypertrophic obesity. GREM1 silencing or BMP4 addition reactivates beige/brown markers even during white adipogenic differentiation. |
BMP4 treatment and GREM1 siRNA silencing in human adipose precursor cells, PPARγ transcriptional activation assays, adipogenic differentiation assays, measurement of beige/brown markers |
Diabetes |
Medium |
25605802
|
| 2018 |
Thymic endothelial cells (ECs) are the critical source of BMP4 for endogenous thymic regeneration; EC-derived BMP4 increases following thymic damage and acts on thymic epithelial cells (TECs) to upregulate Foxn1 and its downstream target Dll4. Abrogating BMP4 signaling pharmacologically or genetically impairs thymic repair. |
Genetic inhibition of EC-specific BMP4 production, pharmacologic BMP4 signaling inhibition, gene expression analysis of Foxn1 and Dll4 in TECs |
Science immunology |
High |
29330161
|
| 2007 |
PTHrP sensitizes mammary mesenchymal cells to BMP4 signaling by upregulating BMP receptor 1A (BMPR1A) expression, enabling mesenchymal response to BMP4 expressed in the ventral epidermis. BMP4 rescues mammary bud outgrowth in PTHrP-/- mice. The combination of PTHrP and BMP4 signaling upregulates Msx2 in mammary mesenchyme to inhibit hair follicle formation. |
PTHrP-/- mouse analysis, BMP4 rescue of PTHrP-/- mammary bud outgrowth, BMPR1A expression analysis by in situ hybridization, Msx2-/- genetic rescue of hair follicle phenotype, BMP signaling assays |
Development (Cambridge, England) |
High |
17301089
|
| 2003 |
Msx1 regulates bmp4 expression in dental mesenchyme, and Msx1/Bmp4 pathway controls alveolar bone formation through sequential induction of Dlx5 and Cbfa1; ectopic Bmp4 expression in Msx1-/- mutants restores Dlx5 expression in dental mesenchyme and rescues both Dlx5 and Cbfa1 expression in alveolar bone. Cbfa1 and Msx1 expression are unaltered in Cbfa1-/- mice, placing Dlx5 and Cbfa1 downstream of Msx1/Bmp4. |
Msx1-/- and Cbfa1-/- mouse mutant analysis, in vivo ectopic Bmp4 expression rescue, in vitro gene induction studies, in situ hybridization |
Mechanisms of development |
High |
14654219
|
| 2021 |
TCF7l2 (Wnt effector) promotes oligodendroglial differentiation by directly repressing Bmp4 transcription; TCF7l2 binds to a Bmp4 gene regulatory element, and TCF7l2 disruption causes oligodendroglial-specific BMP4 upregulation and canonical BMP4 signaling activation in vivo. Compound genetic deletion of oligodendroglial-specific Bmp4 rescues arrested OL differentiation caused by TCF7l2 disruption. |
TCF7l2 conditional knockout in mice, Bmp4 conditional deletion, ChIP-like binding to Bmp4 regulatory element, in vitro OL differentiation assays, immunostaining for BMP4 and signaling markers |
The Journal of neuroscience |
High |
33452226
|
| 2019 |
The epicardial transcription factor Wt1 directly regulates Bmp4 transcription as a target gene; Wt1KO epicardium shows sustained Bmp4 upregulation, and inhibition of the Bmp4 signaling pathway ex vivo and in vivo rescues the cuboidal cell shape phenotype of Wt1KO epicardium, establishing a Wt1→Bmp4 pathway controlling epicardial cell maturation and shape. |
Epicardial-specific Wt1 knockout mouse, transcriptomic analysis, ex vivo and in vivo Bmp4 signaling pathway inhibition, cell morphology analysis |
Development (Cambridge, England) |
Medium |
31624071
|
| 2012 |
CHD7 directly regulates Bmp4 expression by binding an enhancer element downstream of the Bmp4 locus; Chd7 mutant mice show down-regulated and mislocalized Bmp4 expression in the forebrain, impaired apoptosis in the telencephalic midline, and resulting corpus callosum and cortex defects. |
Chd7 nonsense mutant mouse (COA1), in situ hybridization for Bmp4, in vitro CHD7-Bmp4 enhancer binding studies, TUNEL apoptosis assay |
The American journal of pathology |
Medium |
22658483
|
| 2012 |
A conserved 396-bp enhancer ~46 kb upstream of the mouse Bmp4 transcription start site drives expression in incisor epithelium and AER of the developing limb; Pitx homeoproteins directly bind a conserved motif in this enhancer, and mutation of the Pitx binding site abolishes Bmp4 enhancer activity in craniofacial and limb tissues. Pitx2 ChIP confirms direct binding to this Bmp4 enhancer in a dental epithelial cell line. |
Phylogenetic footprinting, transgenic reporter analysis, electrophoretic mobility shift assay (EMSA), in vivo enhancer mutagenesis, Pitx2 chromatin immunoprecipitation (ChIP) |
PloS one |
High |
22701669
|
| 2009 |
Bmp2b has a critical late role in morphogenesis of semicircular canal ducts in the zebrafish inner ear; RNA rescue of early bmp2b(-/-) (swirl) lethality followed by development in the absence of bmp2b demonstrates loss of semicircular canal ducts in adults, with normal ampullae and cristae, revealing a post-embryonic requirement. |
RNA rescue of zebrafish bmp2b null mutants (swirl), adult inner ear morphological analysis, balance assay |
PloS one |
Medium |
19190757
|
| 2021 |
In human epiblast-like organoids, NOGGIN is secreted apically while BMP4 receptors are located basolaterally; NOGGIN transcytoses from the apical extracellular space to the basolateral intercellular space via endocytosis, and this trans-epithelial transport is required for NOGGIN inhibition of BMP4 signaling. |
Self-organizing human gastrulation models, microfluidic flow assays, co-localization analysis of NOGGIN endocytosis route, functional assay demonstrating transcytosis requirement |
Developmental cell |
Medium |
34051144
|
| 2017 |
BMP4 inhibits CYP17A1 (P450c17) expression and C19 steroid (DHEA, DHEA-S, androstenedione) synthesis in human adrenal cells via Smad phosphorylation; the BMP4 system (ligand, receptors BMPRII/ALK3, Smad1/4/5) is expressed in the human adrenal with highest BMP4 levels in zona glomerulosa. Noggin reverses BMP4-mediated suppression of CYP17A1 transcription and DHEA secretion. |
BMP4 treatment of H295R adrenocortical cells, Smad phosphorylation assay, Noggin antagonism, quantitative RT-PCR, protein measurement, immunohistochemistry |
Endocrinology |
Medium |
25868050
|
| 2017 |
BMP4 induces M2 macrophage polarization (as shown by IL-10 expression and secretion) in bladder cancer context; BMP4-containing conditioned media from bladder cancer cells favor monocyte/macrophage polarization toward M2 phenotype in vitro. |
In vitro macrophage polarization assays with recombinant BMP4 and BMP4-containing conditioned media, IL-10 measurement by ELISA, flow cytometry for macrophage markers |
Clinical cancer research |
Medium |
28928159
|
| 2020 |
BMP4 acts as an autocrine mediator to activate canonical BMP-SMAD signaling, upregulating Smad7, which suppresses breast cancer metastasis and sensitizes cancer cells to anoikis. Gene silencing of Bmp4 or Smad7 reverses the anti-metastatic phenotype, and recombinant BMP4 markedly reduces spontaneous metastasis to lung and bone. |
Spontaneous metastasis mouse models, BMP4 KO and overexpression, Smad7 gene silencing, recombinant BMP4 administration, circulating tumor cell quantification |
Cancer research |
Medium |
31941699
|
| 2014 |
BMP4 enhances macrophage foam cell formation by activating BMPR-2/Smad1/5/8 signaling, which inhibits expression of cholesterol transporters ABCA1 and ABCG1; siRNA knockdown of BMPR-2 or inhibition of Smad1/5/8 restores ABCA1 and ABCG1 levels and reduces foam cell formation. |
BMP4 treatment of macrophages, siRNA knockdown of BMPR-2, Smad1/5/8 inhibitor, cholesterol efflux assay, cholesteryl ester:total cholesterol ratio measurement, Western blot |
International journal of molecular sciences |
Medium |
24690996
|
| 2023 |
BMP4 triggers cardiac mesoderm specification by first activating Wnt3 and upregulating Nodal; pSmad1/5 and the WNT effector Tcf3 form a complex that, together with pSmad2/3, activates mesoderm enhancers and Eomes. Eomes and T then form a positive-feedback loop activating Mesp1 and establishing the cardiac mesoderm lineage. |
Mouse ESC differentiation system, pSmad1/5-Tcf3 complex by Co-IP, chromatin accessibility assays for enhancer activation, gene expression time-course analysis |
Development (Cambridge, England) |
Medium |
37082965
|
| 2021 |
Pericytes are the primary pancreatic source of BMP4 and promote functional maturation of β cells; BMP4 produced by pericytes midway through the postnatal period drives expression of core β cell genes and is required for proper insulin production and secretion, as demonstrated by transgenic mouse models and human iPSC differentiation. |
Transgenic mouse models for cell-type-specific BMP4 ablation, human iPSC β cell differentiation, insulin secretion assays, gene expression analysis of β cell maturation markers |
Developmental cell |
High |
34499867
|
| 2019 |
Marcksb controls the secretory process of Bmp2b (zebrafish BMP4-related ligand) via interaction with Hsp70 in vivo; Marcksb deficiency reduces both total and extracellular Bmp2b levels, but maternal-zygotic Marcksb mutants show increased BMP signaling through genetic over-compensation involving sequential upregulation of MARCKS-family members and Hsp70.3. |
Zebrafish morpholino knockdown, maternal-zygotic mutant analysis, Bmp2b secretion assay (total vs. extracellular), pSmad1/5/9 measurement, in vivo Bmp2b imaging |
PLoS genetics |
Medium |
31545789
|
| 2022 |
RUNX2 regulates BMP4 pathway activity by directly inhibiting CHRDL1 (a BMP4 antagonist) transcription; in RUNX2-deficient cells, BMP4 is decreased and CHRDL1 is abnormally elevated. BMP4 treatment rescues osteogenic capacity of RUNX2-haploinsufficient BMSCs. Luciferase reporter experiments show RUNX2 inhibits CHRDL1 transcription, and CHRDL1 inhibits BMP4/Smad signaling. |
CCD patient-derived BMSCs, CRISPR/Cas9 Runx2 mutant MC3T3-E1 cells, luciferase reporter assay, RUNX2 overexpression, BMP4 treatment rescue, immunofluorescence for Smad signaling |
Journal of dental research |
Medium |
35619284
|
| 2024 |
BMP4 signaling from extraembryonic ectoderm (ExE) chorion progenitors is required early for proper differentiation of uncommitted ectoplacental cone cells toward trophoblast giant cells; embryo-derived BMP4 (starting at E7.5) restricts primordial germ cell pool size by favoring differentiation of their extraembryonic mesoderm precursors toward allantois fate, revealing biphasic regulation. |
Temporal single-cell transcriptomics of mouse gastrulation, three-way genetic perturbation targeting ExE BMP4 signaling, embryonic BMP4 signaling, or both; lineage tracing |
Nature |
High |
39294373
|