BicD2 Controls Cell Cycle-Dependent Positioning of Neural Stem cells

Abstract

Radial Glial Progenitors (RGPs) are elongated epithelial cells and are the primary progenitor cell during development of the mammalian neocortex. The RGP cell-cycle and nuclear migration within the ventricular zone (VZ) are tightly interdependent and misregulation of these processes can cause severe neurodevelopmental disorders. Previous knock down studies showed that the dynein activating adaptor protein BicD2 is essential for RGP nuclear migration and mitotic entry. However, the precise in vivo role of BicD2 in RGPs remains unclear. By comparing cell-type specific BicD2 conditional knockout mice, we found the location but not the number of mitotic progenitors was altered. Instead of entering mitosis strictly at the ventricular surface (VS), RGP now entered mitosis across the VZ. Analysis of chromatin morphology, cell morphology and the location of the nuclei and centrosomes suggest these cells are present in two distinct populations. One population appears to be halted in their mitotic progression and nuclear migration while the other is released from the VS and continues through mitosis. Altered RGC morphology is further supported by experiments using organotypic slice culture after ex vivo brain electroporation at early stages of development. Furthermore, immunostaining against BicD2 showed a punctate pattern at the VS and often localized to anti-Pericentrin positive punctae, hinting at additional functions of BICD2 in RGP. Together my data demonstrates surprising effects of BicD2-depletion in RGPs providing new insights into BicD2’s role in the development of the mammalian neocortex.