Affinage

ROBO2

Roundabout homolog 2 · UniProt Q9HCK4

Length
1378 aa
Mass
151.2 kDa
Annotated
2026-06-10
96 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ROBO2 is a single-pass transmembrane receptor for secreted SLIT ligands that transduces predominantly repulsive guidance cues to control axon pathfinding, cell migration, and epithelial tissue morphogenesis (PMID:11163264, PMID:19782674, PMID:15130495). In the nervous system it directs midline and post-crossing commissural axon guidance, dorsal longitudinal tract formation, olfactory and retinal axon targeting, dendrite branching, and target-selective nerve regeneration, often acting cell-autonomously through its SLIT-binding Ig1 domain (PMID:11163264, PMID:20631173, PMID:17715346, PMID:17640525, PMID:19782674, PMID:34916258, PMID:34411419). Downstream, SLIT-ROBO2 signaling reshapes the actin cytoskeleton via Rho-family GTPases — driving Rac1-dependent endothelial lamellipodia, RhoA-dependent myoblast migration, and Cdc42-dependent synaptic actin dynamics — and engages neuronal NADPH oxidase 2 to mediate growth cone collapse (PMID:25894826, PMID:21653616, PMID:31180321, PMID:33191581). ROBO2 also performs non-canonical roles: it acts in trans to inhibit Robo1-mediated repulsion and promote midline crossing, and functions non-cell-autonomously in tendons to promote SLIT cleavage and in the epithelium as a stromal suppressor that restrains TGF-β/Wnt-driven myofibroblast activation (PMID:26186094, PMID:26400093, PMID:30504844). In the urogenital system, SLIT2/ROBO2 restricts the GDNF expression domain and nephrogenic mesenchyme field to position a single ureteric bud and maintain the anti-reflux ureterovesical junction, and ROBO2 disruption causes vesicoureteral reflux in mouse and human (PMID:15130495, PMID:17357069, PMID:26116176, PMID:21949750). In podocytes ROBO2 assembles with nephrin via the adaptor NCK to inhibit actin polymerization and, through a SRGAP1/nonmuscle myosin IIA complex, destabilizes adhesion, so that ROBO2 loss protects against injury-induced foot process effacement (PMID:22840396, PMID:27882344, PMID:32220420). ROBO2 additionally binds non-SLIT ligands — NELL1/2 at a pH- and conformation-gated cryptic FNIII site, and soluble TREM-1 to activate Smad2/3, PI3K/Akt, and ERK signaling in hepatic stellate cells and neurons — and is regulated by alternative splicing, by Robo3.1A-driven lysosomal degradation, and by CD47-mediated sequestration of the E3 ligase ITCH that otherwise targets ROBO2 for ubiquitin-proteasome turnover (PMID:30700556, PMID:35940226, PMID:34750987, PMID:42234329, PMID:31392959, PMID:24936616, PMID:41871254).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2000 High

    Established that ROBO2 is a bona fide SLIT receptor mediating axon repulsion, settling whether it functions alongside Robo1 in midline guidance.

    Evidence Drosophila single/double mutant epistasis showing robo,robo2 double mutants phenocopy slit

    PMID:11163264

    Open questions at the time
    • Did not resolve the distinct downstream effectors of Robo2 versus Robo1
    • Vertebrate receptor specialization not addressed
  2. 2004 High

    Extended ROBO2 function beyond neurons to epithelial morphogenesis by showing SLIT2/ROBO2 limits the GDNF domain to position a single ureteric bud.

    Evidence Slit2 and Robo2 knockout mice with in situ analysis of Gdnf

    PMID:15130495

    Open questions at the time
    • Whether the signal acts by directly attenuating Gdnf or by limiting epithelial-mesenchymal interactions was unresolved
    • Downstream effectors in mesenchyme unknown
  3. 2007 High

    Linked ROBO2 to human disease by showing dominant-negative ROBO2 abrogates signaling and Robo2 haploinsufficiency causes vesicoureteral reflux.

    Evidence Human de novo translocation, in vitro dominant-negative signaling assay, heterozygous Robo2 mice

    PMID:17357069

    Open questions at the time
    • Mechanism connecting reflux to ureterovesical junction defect not yet defined
  4. 2009 High

    Defined receptor-specific roles in vertebrate axon guidance, demonstrating ROBO2 (not Robo1) is the major intraretinal and olfactory targeting receptor and supports dendrite branching.

    Evidence Robo1 vs Robo2 single-KO mouse phenocopy comparisons, Xenopus knockdown/dominant-negative, chick gangliogenesis perturbation

    PMID:17715346 PMID:18278043 PMID:19782674 PMID:19961927

    Open questions at the time
    • Intracellular effectors distinguishing Robo2 from Robo1 not identified
    • How a single receptor partitions axon versus dendrite outputs unclear
  5. 2012 High

    Revealed the cytoskeletal mechanism in podocytes by identifying a ROBO2-NCK-nephrin complex that inhibits actin polymerization.

    Evidence Co-IP, actin polymerization assay, Robo2 KO ultrastructure, Robo2/nephrin epistasis

    PMID:22840396

    Open questions at the time
    • Did not define how actin inhibition translates to foot process architecture
    • Adhesion machinery downstream not yet identified
  6. 2015 High

    Uncovered non-canonical trans and ligand-processing roles, showing Robo2 can inhibit Robo1 in trans and acts non-signaling in tendons to promote Slit cleavage.

    Evidence Drosophila genetics, ectodomain binding, membrane-tethered Slit-N rescue

    PMID:26186094 PMID:26400093

    Open questions at the time
    • Structural basis of Robo2-Robo1 trans interaction not resolved
    • Protease responsible for tendon Slit cleavage unknown
  7. 2016 High

    Mechanistically connected ROBO2 to adhesion by defining a ROBO2/SRGAP1/NMIIA complex that destabilizes podocyte attachment.

    Evidence Co-IP, direct interaction assays, focal adhesion and adhesion assays, podocyte-specific KO injury model

    PMID:27882344

    Open questions at the time
    • How SRGAP1 GAP activity feeds into myosin regulation in vivo not fully traced
  8. 2019 High

    Defined ligand-gating and effector diversification: a cryptic pH-dependent NELL1/2 site, splice-isoform guidance switching, Cdc42-driven synaptic actin control, and a Baiap2-MDM2-p53 epithelial survival axis.

    Evidence Binding/mutagenesis assays, NOVA splice analysis with guidance assays, zebrafish actin imaging with DN-Cdc42, Robo2/p53 double-KO epistasis

    PMID:30700556 PMID:31180321 PMID:31392959 PMID:31534052

    Open questions at the time
    • Physiological trigger unmasking the NELL1/2 site in vivo unclear
    • Whether NELL ligands compete with SLIT functionally not established
  9. 2021 High

    Identified soluble TREM-1 as a non-SLIT ligand and a trans-synaptic Neurexin partner, broadening ROBO2 ligand repertoire and synaptogenic function.

    Evidence Pull-down/mass spectrometry, trans-synaptic binding assays, conditional KO with circuit imaging, regeneration imaging

    PMID:34686348 PMID:34750987 PMID:34916258

    Open questions at the time
    • Structural basis of sTREM-1 and Neurexin binding to ROBO2 not defined
    • Whether these ligands signal through the same intracellular routes as SLIT unknown
  10. 2022 Medium

    Provided the conformational logic for ligand gating, showing the ectodomain shifts from extended to compact under acidic pH to expose the NELL1/2 site.

    Evidence FRET conformational sensors, size exclusion chromatography, isoform binding affinities

    PMID:35940226

    Open questions at the time
    • FRET-based conformational model awaits high-resolution structural confirmation
    • In vivo relevance of acidic-pH gating not demonstrated
  11. 2026 High

    Established post-translational stability control, showing CD47 sequesters the E3 ligase ITCH to block ROBO2 ubiquitination and support tumor cell proliferation.

    Evidence Co-IP, ubiquitination and proteasome assays, knockdown/overexpression, in vivo tumor burden

    PMID:41871254

    Open questions at the time
    • ITCH ubiquitination site on ROBO2 not mapped
    • Whether this regulation operates outside glioblastoma not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse ligand inputs (SLIT, NELL1/2, sTREM-1, Neurexin) and effector branches (Rac1, RhoA, Cdc42, NCK/nephrin, SRGAP1/NMIIA, Nox2, Baiap2/MDM2) are selected in a given cell type to yield repulsion versus adhesion versus survival outputs remains unresolved.
  • No unifying model of ROBO2 signal selection across tissues
  • Cytoplasmic domain interactions linking ligand engagement to each effector branch incompletely mapped
  • Structural basis of receptor activation by SLIT not in corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 2
Partners
BAIAP2CD47ITCHNCKNELL1SLIT1SLIT2SRGAP1
Complex memberships
ROBO2/NCK/nephrin complexROBO2/SRGAP1/NMIIA complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 SLIT2/ROBO2 signaling restricts kidney induction to a single site by limiting the domain of GDNF expression in the nephrogenic mesenchyme. Mouse mutants lacking SLIT2 or ROBO2 develop supernumerary ureteric buds with inappropriately maintained anterior Gdnf expression, demonstrating that the SLIT2/ROBO2 signal is transduced in the nephrogenic mesenchyme. Knockout mouse genetics (Slit2-/- and Robo2-/- mutants), in situ hybridization for Gdnf expression Developmental Cell High 15130495
2000 Drosophila Robo and Robo2 have distinct and complementary roles in midline repulsion; robo,robo2 double mutants phenocopy slit mutants, indicating Robo2 is a functional Slit receptor contributing to midline axon guidance alongside Robo1. Drosophila genetics (single and double mutant analysis), axon trajectory imaging Neuron High 11163264
2015 SLIT2 acting through ROBO1 and ROBO2 promotes retinal neovascularization by driving endothelial cell migration, and is required for both Slit2- and VEGF-induced Rac1 activation and lamellipodia formation. Conditional knockout mice deficient in Slit2, Robo1, and Robo2; endothelial cell migration assays; Rac1 activation assays; lamellipodia imaging Nature Medicine High 25894826
2007 Human ROBO2 disruption by a de novo translocation produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro, and heterozygous Robo2 mouse mutants exhibit vesicoureteral reflux with ureterovesical junction defects. In vitro signaling assay with dominant-negative ROBO2, heterozygous/mosaic Robo2 mouse models, human genetics American Journal of Human Genetics High 17357069
2012 ROBO2 forms a complex with nephrin in kidney podocytes through the adaptor protein NCK. Slit2-Robo2 signaling inhibits nephrin-induced actin polymerization, and loss of Robo2 in mice increases F-actin associated with nephrin, altering podocyte foot process structure. Genetic interaction shows Robo2 loss alleviates abnormal podocyte structural phenotype in nephrin null mice. Co-immunoprecipitation/biochemical pulldown, actin polymerization assay, Robo2 knockout mouse ultrastructure, epistasis analysis in Robo2/nephrin double mutants Cell Reports High 22840396
2016 SLIT2/ROBO2 signaling inhibits nonmuscle myosin IIA (NMIIA) activity and destabilizes podocyte adhesion via a SRGAP1-dependent pathway. MRLC (myosin II regulatory light chain) interacts directly with SRGAP1 and forms a ROBO2/SRGAP1/NMIIA complex in the presence of SLIT2. SLIT2 stimulation decreases focal adhesion formation and reduces podocyte attachment to collagen. Podocyte-specific Robo2 knockout protects mice from hypertension-induced podocyte detachment and albuminuria. Co-immunoprecipitation, direct protein interaction assay, focal adhesion assay, podocyte adhesion assay, conditional KO mouse model, in vivo injury studies JCI Insight High 27882344
2015 Robo2 acts in trans (non-cell-autonomously) to inhibit Slit-Robo1 repulsion in Drosophila pre-crossing commissural axons. Robo2 expressed in midline cells can bind Robo1 via extracellular domains and rescue robo2-dependent midline crossing defects non-cell-autonomously; the extracellular domains required for Robo1 binding are also required for Robo2's midline-crossing promotion activity. Drosophila genetics, gain-of-function/rescue assays, extracellular domain binding experiments eLife High 26186094
2009 Slit1-Robo2 signaling is essential for trigeminal ganglion assembly: placode cells express Robo2 and early migrating cranial neural crest cells express Slit1; perturbation of Robo2 function or depletion of Robo2 or Slit1 disrupts ganglion formation, mimicking neural crest ablation. Chick embryo RNA interference (siRNA), Robo2 function blocking, neural crest ablation, in vivo ganglion imaging Nature Neuroscience High 18278043
2009 N-cadherin acts in concert with Slit1-Robo2 signaling during gangliogenesis. Blocking or augmenting Slit-Robo signaling modulates N-cadherin protein expression on the placodal cell surface, suggesting post-translational regulation of N-cadherin by Slit-Robo2; co-expression of N-cadherin with dominant-negative Robo abrogates the Robo2 loss-of-function phenotype. Chick embryo siRNA knockdown, dominant-negative Robo2, rescue experiments, N-cadherin surface expression assay Development Medium 19934013
2010 Robo1 and Robo2 have distinct specialized roles in post-crossing commissural axon guidance in the mouse spinal cord: Robo2 is required for axons to project away from the floor plate into the lateral funiculus, while Robo1 prevents axonal stalling after crossing. Genetic rescue experiments (Robo3 failure-to-cross rescued largely but not fully by loss of both Robo1 and Robo2) suggest existence of an additional Slit receptor. Mouse genetics, combination KO mutants (Robo1, Robo2, Robo3 single and double/triple mutants), axon trajectory analysis Journal of Neuroscience High 20631173
2007 Robo2 is required for zonal segregation of olfactory sensory neuron (OSN) axons along the dorsoventral axis of the olfactory bulb. Robo2 is expressed in OSNs in a high dorsomedial to low ventrolateral gradient, and in robo-2-/- mice, a subset of OSN axons normally projecting to the dorsal OB mistarget to the ventral region. Slit1 is expressed in the ventral OB consistent with repulsion of Robo2-expressing dorsal axons. Robo2 and Slit1 knockout mice, axon targeting analysis, expression mapping Journal of Neuroscience High 17715346
2007 Slit1a acts through Robo2 to inhibit retinal ganglion cell (RGC) arborization and synaptogenesis in the CNS. Dominant-negative Robo2 expressed in single RGCs phenocopies ast (robo2) mutant increased arborization, and full-length Robo2 rescues it, indicating cell-autonomous action. Genetic analysis shows Slit1a acts partly through Robo2 and partly through Robo2-independent pathways. Zebrafish astray/robo2 mutants, slit1a morphants, single-cell dominant-negative and rescue experiments, time-lapse imaging of arbor development, YFP-Rab3 synapse labeling Neuron High 17640525
2021 Robo2 plays a synaptogenic role in hippocampal CA1, acting postsynaptically in pyramidal neurons for formation of excitatory (but not inhibitory) synapses specifically in proximal dendritic compartments. Robo2 synaptogenic activity involves a trans-synaptic interaction with presynaptic Neurexins, as well as binding to its canonical extracellular ligand Slit. Preventing Robo2-dependent excitatory synapse formation alters place cell properties of adult CA1 neurons. In vivo conditional KO, in vitro trans-synaptic binding assays, 2-photon Ca2+ imaging in behaving mice Cell Reports High 34686348
2019 Robo2 regulates synaptic oxytocin content by affecting actin dynamics via a Slit3-Robo2-Cdc42 pathway. Genetic loss of robo2 decreases synaptic OXT levels and reduces mobility of the actin probe Lifeact-EGFP in OXT synapses, slowing vesicle accumulation. OXT-specific dominant-negative Cdc42 expression links Robo2 to local actin dynamics at synapses. Zebrafish robo2 mutant, live imaging of Lifeact-EGFP and OXT vesicles, dominant-negative Cdc42 expression, cytochalasin-D treatment eLife High 31180321
2015 SLIT/ROBO2 signaling promotes mammary stem cell senescence by inhibiting WNT signaling. Absence of SLIT/ROBO2 signaling leads to increased nuclear β-catenin, repressed expression of p16(INK4a), and delayed mammary stem cell senescence, thereby enhancing stem cell renewal. Robo2 knockout mouse mammary gland analysis, β-catenin nuclear localization, p16(INK4a) expression, stem cell renewal assays Stem Cell Reports Medium 25241737
2018 Epithelial ROBO2 loss activates Robo1+ myofibroblasts and induces TGF-β and Wnt pathways, acting non-autonomously as a stroma suppressor gene. In Robo2-deficient pancreatic epithelium (Pdx1Cre;Robo2F/F mice), enhanced myofibroblast activation, collagen crosslinking, and T-cell infiltration were suppressed by the TGF-β inhibitor galunisertib. Conditional KO (Pdx1Cre;Robo2F/F), cell culture fibroblast activation assays, TGF-β pathway analysis, TGF-β inhibitor rescue Nature Communications High 30504844
2019 Robo2 contains a cryptic binding site for NELL1 and NELL2 in its first fibronectin type III (FNIII) domain, occluded in intact Robo2 at neutral pH. NELL1/2 binding to Robo2 is enabled under acidic conditions or when Robo2 undergoes proteolytic digestion or conformational change; specific amino acids in the first FNIII domain critical for NELL1 binding were identified by mutation analysis. Binding assays (cell surface binding), site-directed mutagenesis of FNIII domain, Robo2 deletion mutants, pH-dependent binding affinity measurements Journal of Biological Chemistry High 30700556
2022 The Robo2 ectodomain undergoes a conformational change from an extended hairpin-like structure to a compact form under acidic pH, which attenuates interactions between Ig-like and FNIII domains to unmask the NELL1/2-binding site. Alternative splicing isoforms of Robo2 have distinct NELL1/2-binding affinities correlated with differences in ectodomain conformation. FRET-based conformational indicators inserted into Robo2 ectodomain, size exclusion chromatography, binding affinity measurements for isoforms Journal of Molecular Biology Medium 35940226
2011 Sclerotome-derived Slit1 drives directional migration and differentiation of Robo2-expressing pioneer myoblasts. Robo2 is expressed downstream of MyoD and Myf5. Loss of Robo2 or sclerotome-derived Slit1 perturbs directional cell migration and fiber formation via RhoA, without affecting myoblast specification. Avian somite inversion experiments, RNAi knockdown of Robo2 and Slit1, RhoA pathway analysis Development Medium 21653616
2015 ROBO2 restricts the nephrogenic field and regulates Wolffian duct-nephrogenic cord separation. In Robo2-null embryos, failure of normal separation of mesenchyme from Wolffian duct/ureteric epithelium exposes mesenchyme to abnormally high proliferative stimuli, expanding the metanephric mesenchyme field and number of nephrogenic cord cells, leading to ectopic ureteric bud outgrowths. This suggests SLIT-ROBO signaling limits epithelial/mesenchymal interactions rather than directly attenuating Gdnf expression. High-resolution 3D imaging of Robo2-null mouse embryos, ex vivo proliferation experiments Developmental Biology Medium 26116176
2011 Robo2 is required for formation of a normal ureteral orifice and maintenance of the anti-reflux mechanism. In Robo2-deficient mice, hydronephrosis results from high-grade vesicoureteral reflux caused by a dilated and incompetent ureterovesical junction. Robo2 is expressed around the developing ureterovesical junction. High-resolution micro-ultrasonography, microbubble ultrasound contrast with percutaneous aspiration, immunolocalization of Robo2 PLoS One High 21949750
2019 Robo2 binds to Baiap2 (IRSp53) through the IRSp53/MIM homology domain in renal epithelial cells. This complex allows Robo2 to phosphorylate MDM2 at Ser166 via Baiap2, maintaining p53 homeostasis. Disruption of the Robo2-Baiap2 complex causes MDM2 dephosphorylation, elevated p53, and p53-mediated cellular senescence, leading to ciliogenesis and polarity defects, cystogenesis. Double KO of Robo2 and p53 rescues all epithelial defects. Co-immunoprecipitation, phosphorylation assays, Robo2 KO and double Robo2/p53 KO mouse models, epithelial polarization and ciliogenesis assays JCI Insight High 31534052
2021 Soluble TREM-1 (sTREM-1) is a novel non-Slit ligand for Robo2. The interaction was identified by pull-down assay followed by mass spectrometry and verified by immunofluorescence. sTREM-1 binding to Robo2 activates downstream Smad2/3 and PI3K/Akt signaling pathways promoting hepatic stellate cell activation and liver fibrosis. Robo2 knockdown inhibited sTREM-1-induced HSC activation and fibrosis. Affinity pulldown followed by mass spectrometry, immunofluorescence colocalization, siRNA knockdown of Robo2 in LX-2 cells, AAV-mediated HSC-specific Robo2 knockdown in mouse fibrosis model, Smad2/3 and PI3K/Akt pathway analysis Journal of Cellular and Molecular Medicine High 34750987
2018 Slit2-Robo2 signaling in hepatic stellate cells (HSCs) promotes fibrogenic protein expression via PI3K/Akt pathway activation, and inhibits HSC migration. Recombinant Slit2 promotes fibrogenic protein expression in HSC line; this effect is abrogated by PI3K/Akt inhibitor. Slit2-stimulated inhibition of migration is abrogated by siRNA knockdown of Robo2. Western blot for fibrogenic proteins, PI3K/Akt pathway inhibitor (LY294002), Robo2 siRNA knockdown, transwell migration assay Life Sciences Medium 29660433
2004 In Drosophila, robo2 and robo3 are necessary for serotonergic neuron differentiation and function independently of their ligand Slit. Loss of robo2 or robo3 causes loss of serotonin transporter (SerT) expression in ~half of neurons, and loss of the transcription factor Eagle (Eg) in serotonergic neurons. robo2 and eg interact genetically to regulate SerT expression, placing Robo2 upstream of Eg in a serotonergic differentiation pathway. Drosophila genetics, SerT and Eg expression analysis in robo2/3 mutants, genetic interaction (robo2;eg double mutant) Development Medium 14973268
2015 In Drosophila, Robo2 plays a non-signaling, non-cell-autonomous role in tendons to promote Slit cleavage, producing a cleaved Slit N-terminal guidance signal essential for muscle-to-tendon guidance. Tendon-specific robo2 RNAi induces muscle patterning defects similar to slit mutants; membrane immobilization of Slit-N on tendons bypasses the requirement for Robo2 in tendons, demonstrating that Robo2's main role is to promote association of Slit with the tendon cell membrane and its subsequent cleavage. Drosophila genetics, tendon-specific RNAi, rescue with membrane-tethered Slit-N, muscle patterning analysis Development High 26400093
2019 Alternative splicing of a conserved microexon in mammalian ROBO2 generates isoforms with distinct axon guidance activities. NOVA splicing factors regulate the developmental expression of ROBO2 variants with small sequence differences. The temporal switch from inhibitory to permissive crossing is partly controlled by expression of these ROBO2 isoforms. Mouse genetics, splice isoform expression analysis, axon guidance behavioral assays, NOVA factor mutant analysis eLife Medium 31392959
2014 Robo3.1A suppresses Slit-mediated repulsion by triggering degradation of Robo2 through recruitment to late endosome/lysosome-dependent degradation pathway. Cotransfection with Robo3.1A significantly reduced Robo2 protein levels in HEK293 cells and cerebellar granule cells. Robo2 and Robo3 colocalize in intracellular vesicles positive for late endosome/lysosome markers. Cotransfection in HEK293 cells, cerebellar granule cell cultures, cell surface Slit-binding assay, immunoprecipitation, immunocytochemistry with organelle markers Journal of Neuroscience Research Medium 24936616
2013 Sim1a and Arnt2 transcription factors contribute to hypothalamo-spinal axon guidance by negatively regulating Robo3a.1 expression, which otherwise blocks Robo2-mediated repulsive axon guidance. The midline displacement phenotype in Sim1a/Arnt2 morphants is suppressed in robo3 mutant embryos; increased Robo3a.1 levels interfere with Robo2 repulsive activity; the N-terminal domain unique to Robo3a.1 mediates this block. Zebrafish morpholino knockdown, robo3 mutant epistasis, robo3a.1 expression analysis, domain-deletion analysis Development Medium 23222439
2020 Neuronal NADPH oxidase 2 (Nox2) acts downstream of Slit2/Robo2 signaling to mediate growth cone collapse, axonal retraction, and repulsive growth cone turning. Slit2 treatment increased growth cone hydrogen peroxide levels via Nox2 activation. astray/nox2 double heterozygote zebrafish larvae exhibited decreased tectal innervation area compared to individual heterozygotes, supporting genetic interaction. Zebrafish RGC cultures, pharmacological Nox inhibition, ROS biosensor imaging, nox2 mutant fish, astray/nox2 double heterozygote in vivo analysis Developmental Neurobiology Medium 33191581
2009 Robo2 is the major receptor required for Slit-mediated intraretinal RGC axon guidance in mice. Robo1 knockout mice have normal intraretinal axon guidance, while Robo2 knockout mice make qualitatively and quantitatively identical pathfinding errors to those in Slit1/Slit2 mutants. Robo1 and Robo2 single knockout mouse comparison, intraretinal axon guidance analysis Developmental Biology High 19782674
2009 In Xenopus RGCs, Slit/Robo2 signaling promotes dendrite branching (but not guidance) primarily via Robo2, while Robo2 and Robo3 act in concert for axon extension and guidance. Loss-of-function by antisense knockdown or dominant-negative Robo2 blocked axon extension and caused misrouting, and also reduced dendrite branching. Antisense morpholino knockdown, dominant-negative Robo2/Robo3 expression, RGC culture, in vitro Slit treatment Mechanisms of Development Medium 19961927
2021 Robo2 in regenerating zebrafish motor axons is required and sufficient for target-selective peripheral nerve regeneration. Robo2 acts in response to glia located at the nerve branch-point, where spatially restricted Slit signaling prevents and corrects axonal errors during regeneration. robo2 function is required cell-autonomously in regenerating axons. Zebrafish live cell imaging, molecular-genetic manipulation (robo2 mutants, overexpression), ablation of glial cells at branch-points Journal of Neuroscience High 34916258
2012 Overexpression of Robo2 in embryonic kidney organ culture leads to reduced ureteric bud branching and decreased glomerular number through a reduction in the number of metanephric mesenchyme (MM) cells surrounding the ureteric bud, without affecting MM proliferation or apoptosis. In vitro embryonic kidney microinjection/electroporation, GFP-Robo2 overexpression, morphometric analysis Biochemical and Biophysical Research Communications Medium 22521888
2020 Loss of Robo2 in podocytes protects adult mice from glomerular injury and foot process effacement. ROBO2 expression in podocytes is upregulated after glomerular injury. Overexpression of ROBO2 in cultured mouse podocytes compromises cell adhesion. Conditional Robo2 KO (podocyte-specific), ultrastructural analysis, injury models (protamine sulfate, nephrotoxic serum), ROBO2 overexpression adhesion assay American Journal of Pathology High 32220420
2020 ROBO2 is expressed in the common nephric duct (CND) and primitive bladder, and its novel binding partner retinaldehyde dehydrogenase-2 (RALDH2) mediates CND migration and fusion with the primitive bladder. Loss of Robo2 causes delayed apoptosis from failure of CND fusion, resulting in abnormal ureter connections. Retinoic acid rescues ureter anomalies in Robo2-/- embryos. Co-immunoprecipitation/binding assay identifying RALDH2 interaction, Robo2 knockout mouse, retinoic acid rescue experiment, apoptosis analysis Developmental Biology Medium 32562756
2021 The Slit-binding Ig1 domain of Robo2 is required for Robo2's midline repulsion activity, lateral axon pathway formation, and proper subcellular localization in Drosophila embryonic neurons in vivo. Robo2ΔIg1 fails to substitute for wild-type Robo2 in both midline repulsion and lateral pathway formation; removal of Ig1 disrupts proper subcellular localization of Robo2, a role not shared by the Ig1 domain of Robo1. CRISPR/Cas9 domain replacement (Robo2ΔIg1 knock-in), axon guidance assays, protein localization analysis Genesis High 34411419
2023 Robo2 actively maintains adult pancreatic islet architecture in β cells. Conditional deletion of Robo2 in adult β cells causes significant loss of islet architecture without affecting β cell identity, maturation, or stress. Conditional Robo2 deletion in adult β cells, histological and immunofluorescence analysis of islet architecture Developmental Biology Medium 37972678
2026 CD47 stabilizes ROBO2 by sequestering the E3 ubiquitin ligase ITCH, thereby blocking ubiquitination and proteasomal degradation of ROBO2. Loss of ROBO2 similarly reduces GBM cell proliferation and migration. CD47 loss impairs GBM cell proliferation and migration in an immune-independent manner. Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, ROBO2 knockdown/overexpression, in vivo tumor burden analysis PNAS High 41871254
2022 Robo2 and Gen1 co-regulate ureteric bud formation by activating the MAPK/ERK signaling pathway. Double disruption of Robo2 and Gen1 synergistically increases CAKUT phenotypes and ectopic UB formation. Robo2 and Gen1 exert synergistic effects on GDNF/RET pathway and downstream MAPK/ERK signaling to promote cell proliferation. Double-mutant mouse model (piggyBac transposon disruption), MAPK/ERK pathway analysis, GDNF/RET signaling measurements Frontiers in Medicine Medium 35071283
2011 In mouse spinal cord, Robo2 is the main receptor for directing axons within dorsal longitudinal tracts, and has a distinct function in repelling neuron cell bodies from the floor plate, distinct from Robo1 (which guides ventral tract axons and prevents midline crossing). Robo1 and Robo2 single KO mouse comparison, reduction-of-function genetics, longitudinal axon trajectory analysis Developmental Biology Medium 21820427
2025 Slit1b/2-Robo2 repulsive signaling in the amacrine cell layer is essential to initiate apical migration of horizontal cells during retinal lamination. Disruption of Robo2 causes basal retention of horizontal cells. Zebrafish CRISPR targeted screening, live imaging of horizontal cell migration, transcriptomics bioRxivpreprint Medium bio_10.1101_2025.07.23.666134
2026 Soluble TREM-1 (sTREM-1) acts as a ligand for ROBO2 in hippocampal neurons, and their interaction activates downstream ERK signaling. Knockdown of neuronal ROBO2 mitigated aging-related hippocampal synaptic degeneration and cognitive impairments. sTREM-1 reduced expression of synaptic proteins via the ROBO2/ERK pathway. In vivo ROBO2 knockdown in hippocampal neurons, ELISA, ERK pathway analysis, senescence accelerated mouse model Molecular Neurobiology Medium 42234329

Source papers

Stage 0 corpus · 96 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 SLIT2-mediated ROBO2 signaling restricts kidney induction to a single site. Developmental cell 301 15130495
2000 Short-range and long-range guidance by slit and its Robo receptors. Robo and Robo2 play distinct roles in midline guidance. Neuron 209 11163264
2015 Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization. Nature medicine 159 25894826
2007 Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux. American journal of human genetics 159 17357069
2002 Pathfinding and error correction by retinal axons: the role of astray/robo2. Neuron 139 11804569
2010 Collaborative and specialized functions of Robo1 and Robo2 in spinal commissural axon guidance. The Journal of neuroscience : the official journal of the Society for Neuroscience 98 20631173
2007 Requirement for Slit-1 and Robo-2 in zonal segregation of olfactory sensory neuron axons in the main olfactory bulb. The Journal of neuroscience : the official journal of the Society for Neuroscience 95 17715346
2009 N-cadherin acts in concert with Slit1-Robo2 signaling in regulating aggregation of placode-derived cranial sensory neurons. Development (Cambridge, England) 73 19934013
2008 Robo2-Slit1 dependent cell-cell interactions mediate assembly of the trigeminal ganglion. Nature neuroscience 72 18278043
2007 Slit1a inhibits retinal ganglion cell arborization and synaptogenesis via Robo2-dependent and -independent pathways. Neuron 71 17640525
2015 Robo2 acts in trans to inhibit Slit-Robo1 repulsion in pre-crossing commissural axons. eLife 69 26186094
2005 Robo2 is required for establishment of a precise glomerular map in the zebrafish olfactory system. Development (Cambridge, England) 62 15716341
2002 Ectopic expression in the giant fiber system of Drosophila reveals distinct roles for roundabout (Robo), Robo2, and Robo3 in dendritic guidance and synaptic connectivity. The Journal of neuroscience : the official journal of the Society for Neuroscience 61 11943815
2012 The lhx2 transcription factor controls thalamocortical axonal guidance by specific regulation of robo1 and robo2 receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 22457488
2014 Common variation near ROBO2 is associated with expressive vocabulary in infancy. Nature communications 56 25226531
2008 ROBO2 gene variants are associated with familial vesicoureteral reflux. Journal of the American Society of Nephrology : JASN 55 18235093
2015 Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract. Human genetics 53 26026792
2012 Inhibitory effects of Robo2 on nephrin: a crosstalk between positive and negative signals regulating podocyte structure. Cell reports 52 22840396
2018 ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling. Nature communications 50 30504844
2016 SLIT2/ROBO2 signaling pathway inhibits nonmuscle myosin IIA activity and destabilizes kidney podocyte adhesion. JCI insight 50 27882344
2011 Robo2 determines subtype-specific axonal projections of trigeminal sensory neurons. Development (Cambridge, England) 44 22190641
2004 Dynamic expression patterns of Robo (Robo1 and Robo2) in the developing murine central nervous system. The Journal of comparative neurology 40 14689480
2021 Synaptogenic activity of the axon guidance molecule Robo2 underlies hippocampal circuit function. Cell reports 39 34686348
2015 ROBO2 restricts the nephrogenic field and regulates Wolffian duct-nephrogenic cord separation. Developmental biology 36 26116176
2012 Robo2--slit and Dcc--netrin1 coordinate neuron axonal pathfinding within the embryonic axon tracts. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 22956848
2009 Robo-2 controls the segregation of a portion of basal vomeronasal sensory neuron axons to the posterior region of the accessory olfactory bulb. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 19906969
2009 Robo2 is required for Slit-mediated intraretinal axon guidance. Developmental biology 31 19782674
2009 Distinct roles for Robo2 in the regulation of axon and dendrite growth by retinal ganglion cells. Mechanisms of development 30 19961927
2019 Temporal regulation of axonal repulsion by alternative splicing of a conserved microexon in mammalian Robo1 and Robo2. eLife 29 31392959
2019 Robo2 contains a cryptic binding site for neural EGFL-like (NELL) protein 1/2. The Journal of biological chemistry 27 30700556
2018 Slit2-Robo2 signaling modulates the fibrogenic activity and migration of hepatic stellate cells. Life sciences 27 29660433
2006 Dynamic changes in Robo2 and Slit1 expression in adult rat dorsal root ganglion and sciatic nerve after peripheral and central axonal injury. Neuroscience research 27 16979769
2014 SLIT/ROBO2 signaling promotes mammary stem cell senescence by inhibiting Wnt signaling. Stem cell reports 26 25241737
2013 Sim1a and Arnt2 contribute to hypothalamo-spinal axon guidance by regulating Robo2 activity via a Robo3-dependent mechanism. Development (Cambridge, England) 25 23222439
2004 robo2 and robo3 interact with eagle to regulate serotonergic neuron differentiation. Development (Cambridge, England) 24 14973268
2012 Slits and Robo-2 regulate the coalescence of subsets of olfactory sensory neuron axons within the ventral region of the olfactory bulb. Developmental biology 23 22981605
2011 Robo1 and Robo2 have distinct roles in pioneer longitudinal axon guidance. Developmental biology 23 21820427
2015 A non-signaling role of Robo2 in tendons is essential for Slit processing and muscle patterning. Development (Cambridge, England) 22 26400093
2013 Frameshift mutations of axon guidance genes ROBO1 and ROBO2 in gastric and colorectal cancers with microsatellite instability. Pathology 22 24247621
2020 Loss of Roundabout Guidance Receptor 2 (Robo2) in Podocytes Protects Adult Mice from Glomerular Injury by Maintaining Podocyte Foot Process Structure. The American journal of pathology 21 32220420
2010 Analysis of the astray/robo2 zebrafish mutant reveals that degenerating tracts do not provide strong guidance cues for regenerating optic axons. The Journal of neuroscience : the official journal of the Society for Neuroscience 21 20943924
2020 Neuronal NADPH oxidase 2 regulates growth cone guidance downstream of slit2/robo2. Developmental neurobiology 20 33191581
2015 Methyl-CpG Binding Protein 2 (Mecp2) Regulates Sensory Function Through Sema5b and Robo2. Frontiers in cellular neuroscience 20 26733807
2022 Genome-Wide Association Study Identifies ROBO2 as a Novel Susceptibility Gene for Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 19 36508697
2011 Sclerotome-derived Slit1 drives directional migration and differentiation of Robo2-expressing pioneer myoblasts. Development (Cambridge, England) 19 21653616
2020 ROBO2 signaling in lung development regulates SOX2/SOX9 balance, branching morphogenesis and is dysregulated in nitrofen-induced congenital diaphragmatic hernia. Respiratory research 18 33208157
2018 Implication of SLIT3-ROBO1/ROBO2 in granulosa cell proliferation, differentiation and follicle selection in the prehierarchical follicles of hen ovary. Cell biology international 16 30288875
2012 Identification and characterisation of STMN4 and ROBO2 gene involvement in neuroblastoma cell differentiation. Cancer letters 16 22906418
2006 Isolation and differential expression of two isoforms of the ROBO2/Robo2 axon guidance receptor gene in humans and mice. Genomics 16 16829019
2022 An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations. Proceedings of the National Academy of Sciences of the United States of America 15 35584116
2019 Robo2 regulates synaptic oxytocin content by affecting actin dynamics. eLife 15 31180321
2013 Down-regulation of ROBO2 expression in prostate cancers. Pathology oncology research : POR 15 24272677
2009 Mutations in the ROBO2 and SLIT2 genes are rare causes of familial vesico-ureteral reflux. Pediatric nephrology (Berlin, Germany) 15 19350278
2022 Circ_ROBO2/miR-186-5p/TRIM14 axis regulates oxidized low-density lipoprotein-induced cardiac microvascular endothelial cell injury. Regenerative therapy 13 35620639
2021 Circ_ROBO2/miR-149 Axis Promotes the Proliferation and Migration of Human Aortic Smooth Muscle Cells by Activating NF-κB Signaling. Cytogenetic and genome research 13 34649241
2013 Heterozygous non-synonymous ROBO2 variants are unlikely to be sufficient to cause familial vesicoureteric reflux. Kidney international 13 23536131
2021 The Slit-binding Ig1 domain is required for multiple axon guidance activities of Drosophila Robo2. Genesis (New York, N.Y. : 2000) 11 34411419
2017 CRISPR-based gene replacement reveals evolutionarily conserved axon guidance functions of Drosophila Robo3 and Tribolium Robo2/3. EvoDevo 11 28588759
2013 The E3 ubiquitin ligase Mycbp2 genetically interacts with Robo2 to modulate axon guidance in the mouse olfactory system. Brain structure & function 10 23525682
2013 Replication of a ROBO2 polymorphism associated with conduct problems but not psychopathic tendencies in children. Psychiatric genetics 10 23982283
2011 Noninvasive assessment of antenatal hydronephrosis in mice reveals a critical role for Robo2 in maintaining anti-reflux mechanism. PloS one 10 21949750
2006 Alternatively spliced Robo2 isoforms in zebrafish and rat. Development genes and evolution 10 16625395
2021 Soluble TREM-1, as a new ligand for the membrane receptor Robo2, promotes hepatic stellate cells activation and liver fibrosis. Journal of cellular and molecular medicine 9 34750987
2021 Robo2 Drives Target-Selective Peripheral Nerve Regeneration in Response to Glia-Derived Signals. The Journal of neuroscience : the official journal of the Society for Neuroscience 9 34916258
2021 Identification of ROBO2 as a Potential Locus Associated with Inhaled Corticosteroid Response in Childhood Asthma. Journal of personalized medicine 8 34442380
2014 Robo3.1A suppresses slit-mediated repulsion by triggering degradation of Robo2. Journal of neuroscience research 8 24936616
2022 Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice. Frontiers in medicine 7 35071283
2021 A Phase 1 first-in-human study of the safety, tolerability, and pharmacokinetics of the ROBO2 fusion protein PF-06730512 in healthy participants. Pharmacology research & perspectives 7 34369667
2019 Intrauterine low-protein diet aggravates developmental abnormalities of the urinary system via the Akt/Creb3 pathway in Robo2 mutant mice. American journal of physiology. Renal physiology 7 31630547
2021 Robo2 Receptor Gates the Anatomical Divergence of Neurons Derived From a Common Precursor Origin. Frontiers in cell and developmental biology 6 34249921
2016 New congenital anomalies of the kidney and urinary tract and outcomes in Robo2 mutant mice with the inserted piggyBac transposon. BMC nephrology 6 27460642
2012 Overexpression of Robo2 causes defects in the recruitment of metanephric mesenchymal cells and ureteric bud branching morphogenesis. Biochemical and biophysical research communications 6 22521888
2023 Inhibition of MAPK/ERK pathway activation rescues congenital anomalies of the kidney and urinary tract (CAKUT) in Robo2PB/+ Gen1PB/+ mice. Biochemical and biophysical research communications 5 36870240
2022 Characterization of enhancer fragments in Drosophila robo2. Fly 5 36217698
2018 Aristolochic acid inhibits Slit2-induced migration and tube formation via inactivation of Robo1/Robo2-NCK1/NCK2 signaling pathway in human umbilical vein endothelial cells. Toxicology letters 5 30381256
2019 Disruption of Robo2-Baiap2 integrated signaling drives cystic disease. JCI insight 4 31534052
2016 Correlations between gastric cancer family history and ROBO2 and RASSF2A gene methylations. Journal of cancer research and therapeutics 4 27461616
2023 Robo2 promotes osteoblast differentiation and mineralization through autophagy and is activated by parathyroid hormone induction. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft 3 36801365
2023 Islet architecture in adult mice is actively maintained by Robo2 expression in β cells. Developmental biology 3 37972678
2022 Conformational Change of the Hairpin-like-structured Robo2 Ectodomain Allows NELL1/2 Binding. Journal of molecular biology 3 35940226
2020 Investigation of DNA variants specific to ROBO2 Isoform 'a' in Irish vesicoureteric reflux patients reveals marked CpG island variation. Scientific reports 3 32041992
2016 ROBO2 gene variants in children with primary nonsyndromic vesicoureteral reflux with or without renal hypoplasia/dysplasia. Pediatric research 3 27002985
2024 Overexpression of miR-25 Downregulates the Expression of ROBO2 in Idiopathic Intellectual Disability. International journal of molecular sciences 2 38612763
2020 ROBO2-mediated RALDH2 signaling is required for common nephric duct fusion with primitive bladder. Developmental biology 2 32562756
2014 Changes in expression of Slit1 and its receptor Robo2 in trigeminal ganglion and inferior alveolar nerve following inferior alveolar nerve axotomy in adult rats: a pilot study. International journal of oral and maxillofacial surgery 2 25457824
2023 SALL4 advances the proliferation and tumor cell stemness of colon cancer cells through the transcription and regulation of ROBO2. Nucleosides, nucleotides & nucleic acids 1 37660281
2023 INF2 and ROBO2 gene mutation in an Indian family with end stage renal failure and follow-up of renal transplantation. Nephrology (Carlton, Vic.) 1 37772439
2026 First-in-Class Small Molecule ROBO2 Binders Identified through Integrated Virtual Screening and Biophysical Validation. bioRxiv : the preprint server for biology 0 41542466
2026 ROBO2 Variants Associated With Atrial Septal Defect Define a Novel Regulatory Element. Circulation. Genomic and precision medicine 0 41693552
2026 Robo2-Nrxn3 Deficiency: A Molecular Hub Linking Excitation-Inhibition Imbalance to the Pathogenesis of Schizophrenia. Schizophrenia bulletin 0 41863359
2026 CD47 stabilizes ROBO2 to regulate glioblastoma progression by preventing ITCH-mediated ubiquitination. Proceedings of the National Academy of Sciences of the United States of America 0 41871254
2026 First-in-Class Small Molecule ROBO2 Binders Identified through Integrated Virtual Screening and Biophysical Validation. Archives of biochemistry and biophysics 0 42162651
2026 Soluble TREM1 Contributes to Aging-Related Neurodegeneration via ROBO2/ERK Pathway. Molecular neurobiology 0 42234329
2026 Stromal and Neuronal Sources of Slit2/3 Ligands in the Adult Pancreas Exhibit Distinct Expression Patterns Independent of Robo2 Receptor Expression in the Islet. bioRxiv : the preprint server for biology 0 42239375
2025 Expression Significance of Serum Circular RNA CDYL and Circular RNA ROBO2 in Patients with Acute Myocardial Infarction and the Value of Their Combined Prediction for Major Adverse Cardiovascular Events. International journal of general medicine 0 41199761
2023 Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates the axon guidance genes robo2 and slit in Drosophila. Research square 0 36824980

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