Functional attenuation of UFD1l, a 22q11.2 deletion syndrome candidate gene, leads to cardiac outflow septation defects in chicken embryos.

Microdeletion of chromosome 22q11.2 is commonly associated with congenital cardiovascular defects that involve development of cranial neural crest cells (NCC) that emigrate through the pharyngeal arches. UFD1l is one of several candidate genes for 22q11.2 deletion syndrome (22q11DS). UFD1l encodes a protein whose yeast counterpart is involved in a ubiquitin-dependent proteolytic degradation pathway; however, the role of UFD1L in NCC development remains unknown. Mouse embryos that lack Ufd1l die before organogenesis. We have therefore studied the function of Ufd1l in the chick system. Chick Ufd1l encoded a 307-amino acid protein that was highly conserved with mouse and human UFD1L. Chick Ufd1l was expressed in the developing neural tube, NCC, and mesenchyme of the head and pharyngeal arch structures, as well as in the conotruncal region (cardiac outflow tract), consistent with the clinical features of 22q11DS. To determine loss-of-function effects of chick Ufd1l in NCC, we infected cardiac NCC with a retrovirus expressing antisense Ufd1l transcripts in chick embryos before their migration. Morphologic analysis of infected embryos at a later developmental stage demonstrated that functional attenuation of chick Ufd1l in cardiac NCC resulted in an increased incidence of conotruncal septation defects. These data suggest that Ufd1l may play a role in cardiac NCC during conotruncal septation.