The hyh mutation uncovers roles for alpha Snap in apical protein localization and control of neural cell fate.

The hyh (hydrocephalus with hop gait) mouse shows a markedly small cerebral cortex at birth and dies postnatally from progressive enlargement of the ventricular system. Here we show that the small hyh cortex reflects altered cell fate. Neural progenitor cells withdraw prematurely from the cell cycle, producing more early-born, deep-layer cerebral cortical neurons but depleting the cortical progenitor pool, such that late-born, upper-layer cortical neurons are underproduced, creating a small cortex. hyh mice carry a hypomorphic missense mutation in the gene Napa encoding soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein alpha (alpha Snap), involved in SNAP receptor (SNARE)-mediated vesicle fusion in many cellular contexts. A targeted null Napa mutation is embryonically lethal. Altered neural cell fate is accompanied by abnormal localization of many apical proteins implicated in regulation of neural cell fate, including E-cadherin, beta-catenin, atypical protein kinase C (aPKC) and INADL (inactivation-no-afterpotential D-like, also known as protein associated with Lin7, or Pals1). Apical localization of the SNARE Vamp7 is also disrupted. Thus, alpha Snap is essential for apical protein localization and cell fate determination in neuroepithelial cells.

Genes that control the size of the cerebral cortex.

Study of the mechanisms that control growth of the cerebral cortex has largely followed by analogy from work in invertebrate systems such as fly and worm. However, the identification of several genes that cause human microcephaly has provided new avenues of investigation into the mechanisms that control cell identity during cerebral cortical development. In vivo studies suggest that many forms of microcephaly result from defects in the control of cell fate: precocious formation of neurons during early developmental stages produces deficiencies in progenitor cells at later stages of neurogenesis, resulting in an overall small cerebral cortex. Also, some of the genes that are mutated in human microcephaly seem to have been targets in the evolution of humans from distant primate ancestors.

Mapping of the mouse hyh gene to a YAC/BAC contig on proximal Chromosome 7.

Mice that are homozygous for the autosomal recessive hydrocephaly with hop gait (hyh) mutation on Chromosome (Chr) 7 have congenital hydrocephalus characterized by an interhemispheric cyst arising from the third ventricle and agenesis of the corpus callosum. Analysis of more than 500 backcross and intercross progeny maps the hyh locus to proximal Chr 7, approximately 13 cM centromeric to its originally reported map position. Analysis of recombinants at several MIT microsatellite markers localized the hyh locus between D7Mit75 and D7Mit56. Development of several new SSLP markers allowed us to refine the hyh candidate interval to a region defined by the cone-rod homeobox ( Crx) gene proximally and D7Mit56 distally. A contig of yeast artificial chromosome (YAC) clones and bacterial artificial chromosome (BAC) clones spanning this entire region has been developed, and a number of potential candidate genes for hyh within this interval have been identified. Gene content is conserved between this region of mouse Chr 7 and human Chr 19q13.3. Physical mapping of the regions around D7Mit75 and D7Mit56 has also determined the order of a number of MIT markers that remain unresolved on the Mouse Genome Database (MGD) map. Our physical map and transcript map may be useful for positional cloning of genes in this unusually gene-rich region of the genome.