1: Dev Biol. 1999 Aug 1;212(1):80-92. 

Neurofibromin deficiency in mice causes exencephaly and is a modifier for
Splotch neural tube defects.

Lakkis MM, Golden JA, O'Shea KS, Epstein JA.

Department of Medicine, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania, 19104, USA.

Neural tube defects are common and serious human congenital anomalies. These
malformations have a multifactorial etiology and can be reproduced in mouse
models by mutations of numerous individual genes and by perturbation of multiple
environmental factors. The identification of specific genetic interactions
affecting neural tube closure will facilitate our understanding of molecular
pathways regulating normal neural development and will enhance our ability to
predict and modify the incidence of spina bifida and other neural tube defects.
Here, we report a genetic interaction between Nf1, encoding the intracellular
signal transduction protein neurofibromin, and Pax3, a transcription factor gene
mutated in the Splotch mouse. Both Pax3 and Nf1 are important for the
development of neural crest-derived structures and the central nervous system.
Splotch is an established model of folate-sensitive neural tube defects, and
homozygous mutant embryos develop spina bifida and sometimes exencephaly. Neural
development is grossly normal in heterozygotes and neural tube defects are not
seen. In contrast, we found a low incidence of neural tube defects in
heterozygous Splotch mice that also harbored a mutation in one Nf1 allele. All
compound homozygotes had severe neural tube defects and died earlier in
embryogenesis than either Nf1(-/-) or Sp(-/-) embryos. We also report occasional
exencephaly in Nf1(-/-) mice and identify more subtle CNS abnormalities in
normal-appearing Nf1(-/-) embryos. Though other genetic loci and environmental
factors affect the incidence of neural tube defects in Splotch mice, these
results establish Nf1 as the first known gene to act as a modifier of neural
tube defects in Splotch. Copyright 1999 Academic Press.

PMID: 10419687 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------