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The ectodermal loss of ARHGAP29 alters epithelial morphology and organization and disrupts murine palatal development
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The ectodermal loss of ARHGAP29 alters epithelial morphology and organization and disrupts murine palatal development

Emily Adelizzi, Lindsey Rhea, Campbell Mitvalsky, Samuel Pek, Bethany Doolittle and Martine Dunnwald
bioRxiv
Cold Spring Harbor Laboratory
03/13/2025
DOI: 10.1101/2025.03.11.642653
PMCID: PMC11952475
PMID: 40161602
url
https://doi.org/10.1101/2025.03.11.642653View
Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Orofacial clefts, including cleft palate (CP), are among the most common types of birth defects. CP specifically, results from a failure of palatal shelf fusion during development. Previous studies have shown that mutations in RhoA GTPase Activating Protein 29 ( ARHGAP29) are linked to CP, yet the role and tissue-specific requirements for ARHGAP29 during palatogenesis remain unknown. Here, we use tissue-specific deletion of Arhgap29 in mice to provide the first direct evidence that ARHGAP29 is essential for proper palatal elevation and fusion. We demonstrate that ectodermal conditional loss of Arhgap29 induces a significant delay in the fusion of palatal shelves at embryonic (E) day 14.5 and an incomplete yet significantly penetrant cleft palate at E18.5 - neither of which are observed when Arhgap29 is lost later in development using K14-Cre. Phenotypic analyses of palatal shelves at E14.5 reveal a disorganized and thicker epithelium at the tip of the shelves. Loss of Arhgap29 increases palate epithelial cell area and upregulates alpha-smooth muscle actin and phospho-myosin regulatory light chain implicating cell morphology and contractility as drivers of CP.Orofacial clefts, including cleft palate (CP), are among the most common types of birth defects. CP specifically, results from a failure of palatal shelf fusion during development. Previous studies have shown that mutations in RhoA GTPase Activating Protein 29 ( ARHGAP29) are linked to CP, yet the role and tissue-specific requirements for ARHGAP29 during palatogenesis remain unknown. Here, we use tissue-specific deletion of Arhgap29 in mice to provide the first direct evidence that ARHGAP29 is essential for proper palatal elevation and fusion. We demonstrate that ectodermal conditional loss of Arhgap29 induces a significant delay in the fusion of palatal shelves at embryonic (E) day 14.5 and an incomplete yet significantly penetrant cleft palate at E18.5 - neither of which are observed when Arhgap29 is lost later in development using K14-Cre. Phenotypic analyses of palatal shelves at E14.5 reveal a disorganized and thicker epithelium at the tip of the shelves. Loss of Arhgap29 increases palate epithelial cell area and upregulates alpha-smooth muscle actin and phospho-myosin regulatory light chain implicating cell morphology and contractility as drivers of CP.This study in mice is the first direct evidence that ARHGAP29 is essential for proper palatal elevation and fusion. Loss of Arhgap29 alters oral epithelial morphology and upregulates contractility proteins.Summary statementThis study in mice is the first direct evidence that ARHGAP29 is essential for proper palatal elevation and fusion. Loss of Arhgap29 alters oral epithelial morphology and upregulates contractility proteins.

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