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Craniofacial deformities, specifically non-syndromic cleft lip with or without palate (NSCL/P), are among the most common class of birth defects. Complex interactions between genetic and environmental factors contribute to the development of NSCL/P. Many genes have been associated with this disease, including ARHGAP29. ARHGAP29, Rho GTPase Activating Protein (GAP) 29, functions in the cyclical regulation of the small GTPase RhoA. Previous studies have identified genetic variants of ARHGAP29 in NSCL/P and have found that ARHGAP29 levels were reduced in mice deficient for Irf6. Data from these studies suggest a role for ARHGAP29 in craniofacial morphogenesis but it remains unknown if ARHGAP29 is required for, or regulates craniofacial development. ARHGAP29 is detected in many tissues, including the oral epithelium. Using the Keratin14-driven Cre-recombinase allele, Krt14Cre ;Arhgap29fl/fl mice displayed a delay in palatal shelf elevation and did not exhibit a cleft palate. We hypothesized that the absence of a cleft palate was due to the late activation of the Krt14-Cre driver. EctCre drives Cre recombinase specifically in the ectoderm a couple of days before the Krt14-Cre. Our results show that EctCre ;Arhgap29fl/fl mice survive to birth and display a non-mendelian pattern of inheritance. Interestingly, EctCre ;Arhgap29fl/fl mice display a fully penetrant kinked tail phenotype, which has been described in other murine models of NSCL/P, and has been attributed to neural tube and skeletal defects. Additionally, at embryonic (E) day 14.5, while all the wild-type embryos showed adherent palatal shelves, 75% of EctCre ;Arhgap29fl/fl mice displayed palatal shelves not elevated or adherent. Our preliminary data also identified one EctCre ;Arhgap29fl/fl embryo out of 3 total analyzed with a cleft palate at E18.5. These data show that ARHGAP29 is required for on-time palatal shelves movement, supporting a role for ARHGAP29 in craniofacial development. © FASEB.


Emily C Adelizzi, Bethany Doolittle, Martine Dunnwald. Arhgap29 is Required for Proper Palatogenesis and its Loss in Ectodermal-Derived Cells Results in a Kinked Tail Phenotype. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022 May;36 Suppl 1

PMID: 35557312

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