Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence

Abstract

Mouse gene inactivation has shown that the transcription factor Sox11 is required for mouse palatogenesis. However, whether Sox11 is primarily involved in the regulation of palatogenesis still remains elusive. In this study, we explored the role of Sox11 in palatogenesis by analyzing the developmental mechanism in cleft palate formation in mutants deficient in Sox11. Sox11 is expressed both in the developing palatal shelf and in the surrounding structures, including the mandible. We found that cleft palate occurs only in the mutant in which Sox11 is directly deleted. As in the wild type, the palatal shelves in the Sox11 mutant undergo outgrowth in a downward direction and exhibit potential for fusion and elevation. However, mutant palatal shelves encounter clefting, which is associated with a malpositioned tongue that results in physical obstruction of palatal shelf elevation at embryonic day 14.5 (E14.5). We found that loss of Sox11 led to reduced cell proliferation in the developing mandibular mesenchyme via Cyclin D1, leading to mandibular hypoplasia, which blocks tongue descent. Extensive analyses of gene expression in Sox11 deficiency identified FGF9 as a potential candidate target of Sox11 in the modulation of cell proliferation both in the mandible and the palatal shelf between E12.5 and E13.5. Finally we show, using in vitro assays, that Sox11 directly regulates the expression of Fgf9 and that application of FGF9 protein to Sox11-deficient palatal shelves restores the rate of BrdU incorporation. Taken together, the palate defects presented in the Sox11 loss mutant mimic the clefting in the Pierre Robin sequence in humans.

MicroRNA-124-3p suppresses mouse lip mesenchymal cell proliferation through the regulation of genes associated with cleft lip in the mouse

“…Wnt1-Cre;Rx3-Cre;Porcn F/Y cKO mice show CL and CP at 100%.CLO or CLP25 Ptch1 patched 1[31]23900075 Wnt1-Cre;Ptch1 cKO mice show CL or midfacial cleft at E12.5. Embryos die by E12.5.CL or midfacial cleft26 Ptpn11 protein tyrosine phosphatase, non-receptor type 11[32]19706403 Wnt1-Cre;Ptpn11 Tg/+ (gain of function) mice show CL and CP at 21%.CLP27 Rpgrip1l Rpgrip1-like[33–35]17553904; 17558409; 21677750Homozygous null mutant mice show CL.CLO28 Satb2 special AT-rich sequence binding protein 2[36, 37]16960803; 16751105Homozygous null mutant mice show CL and CP.CLP29 Sox11 SRY-box 11[38, 39]15254231; 26826126Homozygous null mutant mice and EIIa-Cre;Sox11 cKO mice show either unilateral or bilateral CL at 70% and either anterior or complete CP at 100%.CLP or CPO30 Sp8 trans-acting transcription factor 8[40]23872235 FoxG1-Cre;Sp8 c KO mice (5 out of 13) exhibit CLO.CLO31 Tbc1d32 TBC1 domain family, member 32[13]25807483Homozygous mutant mice show CL and CP. Mutation is ENU-induced single point mutation.CLO or CLP32 Tbx1 T-box 1[41]19557177 Ap2a IRESCre/+ ;COET conditional Tbx1 overexpression mice exhibit bilateral CL.…”

Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling

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Genetics and signaling mechanisms of orofacial clefts

“…Iwata, Tung, et al, 2012). Sox11 also regulates proliferation in the palatal shelves through Fgf9 , which can be activated to rescue growth defects in Sox11 ‐/‐ palate in vitro (H. Huang et al, 2016).…”