Neural-specific inactivation of ShcA results in increased embryonic neural progenitor apoptosis and microencephaly.
Brain size is precisely regulated during development and involves coordination of neural progenitor cell proliferation, differentiation, and survival. The adapter protein ShcA transmits signals from receptor tyrosine kinases via MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) and PI3K (phosphatidylinositol 3-kinase)/Akt signaling pathways. In the CNS, ShcA expression is high during embryonic development but diminishes as cells differentiate and switches to ShcB/Sck/Sli and ShcC/N-Shc/Rai. To directly test ShcA function in brain development, we used Cre/lox technology to express a dominant-negative form of ShcA (ShcFFF) in nestin-expressing neural progenitors. ShcFFF-expressing mice display microencephaly with brain weights reduced to 50% of littermate controls throughout postnatal and adult life. The cerebrum appeared most severely affected, but the gross architecture of the brain is normal. Body weight was mildly affected with a delay in reaching mature weight. At a mechanistic level, the ShcFFF microencephaly phenotype appears to be primarily attributable to elevated apoptosis levels throughout the brain from embryonic day 10.5 (E10.5) to E12, which declined by E14.5. Apoptosis remained at normal basal levels throughout postnatal development. Proliferation indices were not significantly altered in the embryonic neuroepithelium or within the postnatal subventricular zone. In another approach with the same nestin-Cre transgene, conditional deletion of ShcA in mice with a homozygous floxed shc1 locus also showed a similar microencephaly phenotype. Together, these data suggest a critical role for ShcA in neural progenitor survival signaling and in regulating brain size.
McFarland
Karen N
KN
Department of Pathology (Neuropathology), Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.
Wilkes
Steven R
SR
Koss
Sarah E
SE
Ravichandran
Kodi S
KS
Mandell
James W
JW
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D001925:Brain Damage, Chronic / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002470:Cell Survival; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1