Abstract
ABSTRACTOmphalocele 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.
Highlights
Ventral body wall closure is a critical process to store internal abdominal organs in the body cavity and to establish the umbilical ring at the central point of the ventral body
The transition from coelomic epithelial cells (CECs) of the primary abdominal wall (PAW) to rounded mesothelial progenitor cells was impaired and the inner coelomic surface of the PAW showed relatively smooth in Six4-/-;Six5-/- embryos at E11.25
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, resulting in omphalocele
Summary
Ventral body wall closure is a critical process to store internal abdominal organs in the body cavity and to establish the umbilical ring at the central point of the ventral body. Patients with upper-type omphalocele show loss of the anterior body wall and sternum and have cardiac anomaly and diaphragm hernia, while patients with lower-type omphalocele have defects in the anus, bladder, and external genitalia (Duhamel, 1963; Klein et al, 1981; Stoll et al, 2008). Middle-type omphalocele, which is predominant in large omphalocele patients, usually exhibits no other complex anomalies in other organs with the exception of loss of the anterior abdominal wall (Duhamel, 1963; Klein et al, 1981; Toress et al, 2015). The genetic factors associated with each type of large omphalocele and the cellular mechanisms of omphalocele formation are still largely unknown
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