Journal of pediatric surgery · 2026
HABP4/VIM-mediated focal adhesion assembly regulates enteric neural crest cell migration via the FAK/SRC pathway.
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Lin Huifang, Xiao Jun, Zheng Ziyi, Zhou Jie, Li Renfu, Shen Zhiyong, Li Honglin, Feng Jiexiong, Chen Feng
Аннотация
BACKGROUND: The enteric nervous system (ENS) arises from enteric neural crest cells (ENCCs), and defects in this process can lead to Hirschsprung's disease (HSCR), a congenital disorder characterized by the absence of enteric neurons in the distal colon. Our previous work has identified HABP4 as a potential susceptibility gene for HSCR; however, the mechanisms by which it regulates ENS development remain unclear.
METHODS: Single-cell RNA sequencing combined with immunofluorescence staining was used to characterize the spatiotemporal expression pattern of HABP4 in mouse intestinal tissues. HABP4-knockdown human embryonic stem cell-derived neural crest cells (hESC-derived NCCs) were generated to evaluate its role in ENS development, and cell migration was assessed using Transwell assays. Protein-protein interaction network analysis integrated with transcriptomic profiling was performed to identify HABP4-interacting partners and downstream signaling pathways, which were further validated by AlphaFold-based structural modeling and co-immunoprecipitation. In addition, pharmacological rescue experiments were conducted to examine the functional involvement of key downstream effectors, and the pathogenicity of HABP4 variants identified in HSCR patients was further evaluated.
RESULTS: HABP4 was highly and specifically expressed in ENCCs. Knockdown of HABP4 significantly impaired the migratory capacity of hESC-derived NCCs. Transcriptomic analysis revealed significant enrichment of focal adhesion-related gene sets following HABP4 knockdown. Mechanistically, HABP4 interacted with VIM to promote focal adhesion assembly and activate the FAK/SRC signaling cascade, thereby facilitating ENCCs migration. Notably, treatment with a focal adhesion kinase (FAK) agonist partially rescued the migration defects induced by HABP4 knockdown, and the HABP4 variant (R379W) identified in HSCR patients was found to impair ENCCs migration.
CONCLUSION: HABP4 is localized at the leading edge of migrating ENCCs, where it interacts with VIM to promote focal adhesion assembly and activate FAK/SRC signaling.
METHODS: Single-cell RNA sequencing combined with immunofluorescence staining was used to characterize the spatiotemporal expression pattern of HABP4 in mouse intestinal tissues. HABP4-knockdown human embryonic stem cell-derived neural crest cells (hESC-derived NCCs) were generated to evaluate its role in ENS development, and cell migration was assessed using Transwell assays. Protein-protein interaction network analysis integrated with transcriptomic profiling was performed to identify HABP4-interacting partners and downstream signaling pathways, which were further validated by AlphaFold-based structural modeling and co-immunoprecipitation. In addition, pharmacological rescue experiments were conducted to examine the functional involvement of key downstream effectors, and the pathogenicity of HABP4 variants identified in HSCR patients was further evaluated.
RESULTS: HABP4 was highly and specifically expressed in ENCCs. Knockdown of HABP4 significantly impaired the migratory capacity of hESC-derived NCCs. Transcriptomic analysis revealed significant enrichment of focal adhesion-related gene sets following HABP4 knockdown. Mechanistically, HABP4 interacted with VIM to promote focal adhesion assembly and activate the FAK/SRC signaling cascade, thereby facilitating ENCCs migration. Notably, treatment with a focal adhesion kinase (FAK) agonist partially rescued the migration defects induced by HABP4 knockdown, and the HABP4 variant (R379W) identified in HSCR patients was found to impair ENCCs migration.
CONCLUSION: HABP4 is localized at the leading edge of migrating ENCCs, where it interacts with VIM to promote focal adhesion assembly and activate FAK/SRC signaling.