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

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.

Distinct Genetic Signatures among Pilocytic Astrocytomas Relate to Their Brain Region Origin

“…Both PAX3 and IRX2 are expressed in the developing hindbrain (37)(38)(39). In addition, PAX3 is one of the development signals critical for proper hindbrain differentiation (40), and PAX3-deficient mice (Splotch mutant mice) exhibit neural tube closure defects and abnormal brain development (41). IRX2 and IRX5 are members of the Iroquois class of homeobox genes, and IRX2 is involved in vertebrate cerebellar development (39).…”

Neurofibromin Regulates Neural Stem Cell Proliferation, Survival, and Astroglial Differentiation In Vitro and In Vivo

“…As has been proposed previously for other genes involved in astroglial cell differentiation, such as p27 kip1 (CasacciaBonnefil et al, 1999) or Pten (Groszer et al, 2001), reduced or absent expression of the neurofibromin tumor suppressor results in abnormal brain development. In this regard, 12.5% of Nf1Ϫ/Ϫ embryos exhibited gross defects of cranial neural tube closure, including exencephaly (Lakkis et al, 1999).…”

Exchange Factors of the RasGRP Family Mediate Ras Activation in the Golgi

“…GAP proteins catalyze the hydrolysis of GTP into GDP, thus facilitating the transition of Ras proteins from the active to the inactive state (22). This biological role is crucial for the proper balance of signal transduction outputs, as demonstrated by the embryonic and pathological defects associated with the inactivation of Ras GAP proteins such as p120 RasGAP or NF1 (23)(24)(25)(26). The contribution of these inhibitory factors in the specific activation of Ras proteins in different subcellular compartments is as yet unknown.…”