Integrin αvβ3 and thyroid hormones promote expansion of progenitors in embryonic neocortex

Neocortex expansion during evolution is associated with the enlargement of the embryonic subventricular zone, which reflects an increased self-renewal and proliferation of basal progenitors. In contrast to human, the vast majority of mouse basal progenitors lack self-renewal capacity, possibly due to lack of a basal process contacting the basal lamina and downregulation of cell-autonomous production of extracellular matrix (ECM) constituents. Here we show that targeted activation of the ECM receptor integrin alpha(v)beta(3) on basal progenitors in embryonic mouse neocortex promotes their expansion. Specifically, integrin alpha(v)beta(3) activation causes an increased cell cycle re-entry of Pax6-negative, Tbr2-positive intermediate progenitors, rather than basal radial glia, and a decrease in the proportion of intermediate progenitors committed to neurogenic division. Interestingly, integrin alpha(v)beta(3) is the only known cell surface receptor for thyroid hormones. Remarkably, tetrac, a thyroid hormone analog that inhibits the binding of thyroid hormones to integrin alpha(v)beta(3), completely abolishes the intermediate progenitor expansion observed upon targeted integrin alpha(v)beta(3) activation, indicating that this expansion requires the binding of thyroid hormones to integrin alpha(v)beta(3). Convergence of ECM and thyroid hormones on integrin alpha(v)beta(3) thus appears to be crucial for cortical progenitor proliferation and self-renewal, and hence for normal brain development and the evolutionary expansion of the neocortex.