Mice doubly deficient in Six4 and Six5 show ventral body wall defects reproducing human omphalocele

Abstract

Omphalocele is a human congenital anomaly in ventral body wall closure and may be caused by impaired formation of the primary abdominal wall (PAW) and/or defects in abdominal muscle development. Here, we report that mice doubly deficient in homeobox genes Six4 and Six5 showed the same ventral body wall closure defects as those seen in human omphalocele. SIX4 and SIX5 were localized in surface ectodermal cells and somatic mesoderm-derived mesenchymal and coelomic epithelial cells (CECs) in the PAW. Six4−/−;Six5−/− fetuses exhibited a large omphalocele with protrusion of both the liver and intestine, or a small omphalocele with protrusion of the intestine, with complete penetrance. The umbilical ring of Six4−/−;Six5−/− embryos was shifted anteriorly and its lateral size was larger than that of normal embryos at the E11.5 stage, before the onset of myoblast migration into the PAW. The proliferation rates of surface ectodermal cells in the left and right PAW and somatic mesoderm-derived cells in the right PAW were lower in Six4−/−;Six5−/− embryos than those of wild-type embryos at E10.5. The transition from CECs of the PAW to rounded mesothelial progenitor cells was impaired and the inner coelomic surface of the PAW was relatively smooth in Six4−/−;Six5−/− embryos at E11.25. Furthermore, Six4 overexpression in CECs of the PAW promoted ingression of CECs. Taken together, our results suggest that Six4 and Six5 are required for growth and morphological change of the PAW, and the impairment of these processes is linked to the abnormal positioning and expansion of the umbilical ring, which results in omphalocele.

Upregulation of SIX4 indicates poor clinical outcome and promotes tumor growth and cell metastasis in esophageal squamous cell carcinoma

“…For example, Six4 can regulate male sex determination and mouse gonadal development 16 . Mice doubly deficient in homeobox genes Six4 and Six5 showed ventral body wall defects as those seen in human omphalocele 17 . In this study, SIX4 was upregulated in ESCC tissues and cells.…”

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

“…In congenital malformations affecting the body wall including omphalocele and gastroschisis, the future ventral abdominal body wall fails to form properly, resulting in internal organ protrusion and herniation of abdominal muscles, among other phenotypes (Boylan et al, 2020; Brewer and Williams, 2004; Sadler and Feldkamp, 2008). Among the candidate factors involved in this process is TGF-β signaling that has been repeatedly associated with Hand2 function and midline migration (Gays et al, 2017; Laurent et al, 2017; Yin et al, 2010), as well as Six4 and Six5 (Takahashi et al, 2018). Further, Hand2 regulates extracellular matrix components including repression of Fibronectin production, disruption of which lead to migration defects in the heart and prospective visceral mesothelium (Garavito-Aguilar et al, 2010; Yin et al, 2010).…”

The SIX Family of Transcription Factors: Common Themes Integrating Developmental and Cancer Biology

“…However, Six4 has been found to cooperate with other SIX family members in several developmental processes. Both Six5 and Six4 were identified to function together during vertebrate body wall development where loss of both genes resulted in omphalocele ( Takahashi et al, 2018 ). Further mouse compound knock-out studies have uncovered Six4 functional cooperation with Six1 during myogenesis ( Grifone et al, 2005 ; Relaix et al, 2013 ; Wurmser et al, 2020 ), gonadogenesis ( Fujimoto et al, 2013 ); thymus development ( Zou et al, 2006 ), neurogenesis ( Konishi et al, 2006 ; Chen et al, 2009 ), and kidney development ( Kobayashi et al, 2007 ; Xu and Xu, 2015 ).…”