α-Klotho regulates mouse embryonic neural stem cell proliferation and differentiation.

A longevity factor α-Klotho has been shown to be neuroprotective and enhance brain function. However, it has not been elucidated whether α-Klotho is involved in the embryonic brain development. To address this, we investigated whether α-Klotho regulates embryonic neural stem cell proliferation and differentiation. We found that α-Klotho is expressed in the mouse embryonic brain and neural stem cells isolated from the embryonic day 13.5 brains. When α-Klotho was knocked down in the embryonic neural stem cells, basal level of apoptosis increased while proliferation decreased. Overexpression of membrane-bound or secreted form of α-Klotho promoted proliferation of the mouse embryonic neural stem cells. Knockdown of α-Klotho suppressed the phosphorylation of Akt and ERK, suggesting that α-Klotho may promote neural stem cell survival and proliferation by activating signaling pathway involving Akt and ERK. In addition, knockdown of α-Klotho suppressed differentiation of embryonic neural stem cells into neurons or oligodendrocytes but not astrocytes. These results suggest that α-Klotho may have a role in neuronal development by promoting neural stem cell survival, proliferation and differentiation.