Ryuichi Sakai* !, Jeffrey T. Henderson* !, John P. O'Bryan #, Andrew J.Elia ^, Tracy M. Saxton # and Tony Pawson #

!  Samuel Lunenfeld Research Institute, Mount Sinai Hospital,
   Program in Molecular Biology and Cancer , 600 University Ave., Toronto, Ontario M5G-1X5
^  Amgen Institute, 620 University Avenue, suite 706, Toronto, Ontario, Canada M5G 2C1
#  NIEHS/NIH , 111 TW Alexander Drive, P.O. Box 12333, Research Triangle Park NC 27709
* Authors contributed equally to this work.

Neuron 28, 819-833, 2000

Abstract

Shc proteins possess two phosphotyrosine (pTyr) recognition modules, the SH2 and PTB domains, and serve a scaffolding function in signaling by a variety of receptor tyrosine kinases. There are three known mammalian Shc genes, ShcA, ShcB and ShcC, of which ShcB and ShcC are primarily expressed in the nervous system. Here, we show that ShcB encodes a 68 kDa polypeptide with an extended proline-rich amino-terminus. We have generated null mutations in both the ShcB and ShcC genes, and have obtained viable mice lacking either ShcB or ShcC, or both gene products. ShcB-deficient animals exhibit a specific loss of substantial populations of peptidergic and non-peptidergic nociceptive sensory neurons which is not enhanced by additional loss of ShcC. Mice lacking both ShcB and ShcC exhibit a significant loss of neurons within the superior cervical ganglia during the latter part of development which is not observed in either mutant alone. The results indicate that these Shc family members possess both unique and overlapping functions in regulating mammalian neural development, and suggest a physiological role for ShcB/ShcC in TrkA signaling.

Full Paper