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

Nature Genetics volume 36, pages 264–270 (2004)Cite this article

A Corrigendum to this article was published on 01 April 2004

Abstract

The hyh (hydrocephalus with hop gait) mouse shows a markedly small cerebral cortex at birth and dies postnatally from progressive enlargement of the ventricular system1,2. 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 (αSnap), 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, β-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, αSnap is essential for apical protein localization and cell fate determination in neuroepithelial cells.

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Figure 1: Positional identification of the hyh mutation.
Figure 2: M105I αSnap is indistinguishable from wild-type αSnap in vitro.
Figure 3: Abnormal cell fates in cerebral cortex of hyh mutants.
Figure 4: Precocious neurogenesis and progenitor depletion in cortex of hyh mutants.
Figure 5: Abnormalities of the ventricular neuroepithelium in hyh mutants.

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Acknowledgements

We thank M. Davisson and H. Sweet for their help and collaboration on early genetic mapping; T. Thompson for assistance with transgenic mouse production; U. Berger for in situ hybridizations; S.-H. Cho for help with confocal imaging; J. Lauer for help with SNARE complex assays; the Developmental Studies Hybridoma Bank for antibodies; W. Zhong, T. Galli, M. Ogawa, J. Cunningham and E. Morrissey for providing antisera; and K. Allen for use of several slides pictured in Figure 3 and for her ongoing enthusiasm and support of this project. T.H.C. was supported by the US National Institutes of Health Medical Scientist Training Program and the Adams/Quan Fellowship. S.K. is supported by a Helen Hay Whitney Postdoctoral fellowship. Transgenic work was supported by the Mental Retardation Research Center at Children's Hospital, Boston. P.I.H. and C.A.W. were supported by grants from the US National Institute of Neurological Disease and Stroke. P.I.H. is a W.M. Keck Foundation Distinguished Young Scholar. C.A.W. is an Investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Teresa H Chae and Seonhee Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Beth Israel Deaconess Medical Center and Department of Neurology and Program in Neuroscience, Howard Hughes Medical Institute, Harvard Medical School, HIM 816, 4 Blackfan Circle, Boston, 02115, Massachusetts, USA

    Teresa H Chae, Seonhee Kim & Christopher A Walsh

  2. Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Karla E Marz & Phyllis I Hanson

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  1. Teresa H Chae
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  2. Seonhee Kim
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  4. Phyllis I Hanson
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Correspondence to Christopher A Walsh.

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Chae, T., Kim, S., Marz, K. et al. The hyh mutation uncovers roles for αSnap in apical protein localization and control of neural cell fate. Nat Genet 36, 264–270 (2004). https://doi.org/10.1038/ng1302

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