Elsevier

Developmental Biology

Volume 212, Issue 1, 1 August 1999, Pages 80-92
Developmental Biology

Regular Article
Neurofibromin Deficiency in Mice Causes Exencephaly and Is a Modifier for Splotch Neural Tube Defects

https://doi.org/10.1006/dbio.1999.9327Get rights and content
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Abstract

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.

Keywords

exencephaly
spina bifida
Nf1
Pax3
dorsal root ganglia

Cited by (0)

1

Present address: Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104.

2

To whom correspondence should be addressed at 954 BRBII, 421 Curie Boulevard, Philadelphia, PA 19104. Fax: (215) 573-2094. E-mail: [email protected].