Induced haploinsufficiency of Kit receptor tyrosine kinase impairs brain development.

Abstract

Kit receptor tyrosine kinase is highly expressed in the developing mammalian brain, yet little is known about its contribution to neural cell development and function. Here we introduced a brain-specific conditional Kit loss-of-function mutation in mice and observed severe hypoplasia of the central nervous system. This was accompanied by an increase in apoptotic cell death in the early embryonic brain and the gradual loss of the self-renewal capacity of neuronal stem/precursor cells. A single copy of the brain-specific conditional Kit loss-of-function allele resulted in the observed phenotype, including impaired in vitro differentiation of neural cells from Kit-haploinsufficient embryonic stem (ES) cells. Our findings demonstrate that Kit signaling is required for the early development of neural cells. This potentially novel Kit-haploinsufficient lethal phenotype may represent an embryonic lethal phenomenon previously unobserved because of its dominantly acting nature.