EXPRESSION AND ACTIVATION OF SH2 PTB-CONTAINING SHCA ADAPTER PROTEIN REFLECTS THE PATTERN OF NEUROGENESIS IN THE MAMMALIAN BRAIN/

The adult mammalian brain comprises many functionally distinct neurona l types, which are generated during development as a result of a coord inated signaling cascade that drives neuroblasts from proliferation in to differentiation, We investigated whether and how ShcA adaptor prote ins, which are known to function as initiators of the Ras signaling ca scade in various nonneuronal systems where they have been considered t o be expressed ubiquitously, are involved in the proliferative and dif ferentiative phases of the developing brain, We found that in the fore brain expression and activation of ShcA proteins were strictly regulat ed during embryonic development, both temporally and spatially, The mR NAs encoded by the ShcA gene were expressed exclusively within an area to which active proliferation of immature neuroblasts was confined, t he ventricular zone, In postnatal and adult brain, ShcA mRNAs and prot eins were present only faintly, In the adult olfactory epithelium, in which neuronal cell renewal occurs throughout life, ShcA remained stro ngly expressed, These phenomena were peculiar to ShcA, since Grb2 adap tor protein remained expressed at constant level throughout developmen t, The embryonically expressed ShcA proteins were functionally active, since p52(ShcA) became phosphorylated on tyrosine and associated with Grb2 following intraventricular injection of epidermal growth factor in the embryonic brain, Our data indicate that, through an orderly pat tern of expression, ShcA gene products may play a role in the control of the switch between proliferation and differentiation of brain neuro blasts.