AUTHOR=Luo Songyuan , Liu Zhixu , Bian Qian , Wang Xudong 

TITLE=Ectomesenchymal Six1 controls mandibular skeleton formation

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1082911

DOI=10.3389/fgene.2023.1082911

ISSN=1664-8021

ABSTRACT=<p>Craniofacial development requires intricate cooperation between multiple transcription factors and signaling pathways. Six1 is a critical transcription factor regulating craniofacial development. However, the exact function of Six1 during craniofacial development remains elusive. In this study, we investigated the role of Six1 in mandible development using a <italic>Six1</italic> knockout mouse model (<italic>Six1</italic><sup><italic>−/−</italic></sup>) and a cranial neural crest-specific, <italic>Six1</italic> conditional knockout mouse model (<italic>Six1</italic><sup><italic>f/f</italic></sup><italic>; Wnt1-Cre</italic>). The <italic>Six1</italic><sup><italic>−/−</italic></sup> mice exhibited multiple craniofacial deformities, including severe microsomia, high-arched palate, and uvula deformity. Notably, the <italic>Six1</italic><sup><italic>f/f</italic></sup><italic>; Wnt1-Cre</italic> mice recapitulate the microsomia phenotype of <italic>Six1</italic><sup><italic>−/−</italic></sup> mice, thus demonstrating that the expression of <italic>Six1</italic> in ectomesenchyme is critical for mandible development. We further showed that the knockout of <italic>Six1</italic> led to abnormal expression of osteogenic genes within the mandible. Moreover, the knockdown of <italic>Six1</italic> in C3H10 T1/2 cells reduced their osteogenic capacity <italic>in vitro</italic>. Using RNA-seq, we showed that both the loss of Six1 in the E18.5 mandible and Six1 knockdown in C3H10 T1/2 led to the dysregulation of genes involved in embryonic skeletal development. In particular, we showed that Six1 binds to the promoter of <italic>Bmp4</italic>, <italic>Fat4</italic>, <italic>Fgf18,</italic> and <italic>Fgfr2</italic>, and promotes their transcription. Collectively, our results suggest that Six1 plays a critical role in regulating mandibular skeleton formation during mouse embryogenesis.</p>