Induced haploinsufficiency of Kit receptor tyrosine kinase impairs brain development

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• Kit receptor tyrosine kinase (RTK) is highly expressed in the developing mammalian brain.
• Its precise role in neural cell development and function remains largely unknown.

Purpose of the Study:

• To investigate the contribution of Kit signaling to neural cell development and function.
• To characterize the consequences of Kit loss-of-function in the developing brain.

Main Methods:

• Generation of a brain-specific conditional Kit loss-of-function mutation in mice.
• Analysis of central nervous system development, cell apoptosis, and stem/precursor cell self-renewal capacity.
• In vitro differentiation assays using neural cells from Kit-haploinsufficient embryonic stem cells.

Main Results:

• Severe hypoplasia of the central nervous system was observed in mice with the Kit loss-of-function mutation.
• Increased apoptotic cell death occurred in the early embryonic brain.
• A gradual loss of self-renewal capacity in neuronal stem/precursor cells was noted.
• Impaired in vitro differentiation of neural cells from Kit-haploinsufficient embryonic stem cells.

Conclusions:

• Kit signaling is essential for the early development of neural cells.
• A novel, dominantly acting, embryonic lethal phenotype associated with Kit-haploinsufficiency may have been previously unrecognized.