Cep120 and TACCs Control Interkinetic Nuclear Migration and the Neural Progenitor Pool

Abstract

Centrosome- and microtubule-associated proteins have been shown to be important for maintaining the neural progenitor pool during neocortical development by regulating the mitotic spindle. It remains unclear whether these proteins may control neurogenesis by regulating other microtubule-dependent processes such as nuclear migration. Here, we identify Cep120, a centrosomal protein preferentially expressed in neural progenitors during neocortical development. We demonstrate that silencing Cep120 in the developing neocortex impairs both interkinetic nuclear migration (INM), a characteristic pattern of nuclear movement in neural progenitors, and neural progenitor self-renewal. Furthermore, we show that Cep120 interacts with transforming acidic coiled-coil proteins (TACCs) and that silencing TACCs also causes defects in INM and neural progenitor self-renewal. Our data suggest a critical role for Cep120 and TACCs in both INM and neurogenesis. We propose that sustaining INM may be a mechanism by which microtubule-regulating proteins maintain the neural progenitor pool during neocortical development.

Myosin II is required for interkinetic nuclear migration of neural progenitors

“…Remarkably, very little is known about this machinery, in contrast to that mediating the basal-to-apical (bl3ap) leg of INM, about which significant insight has been obtained recently. Thus, consistent with earlier studies implicating microtubules in INM (2), recent studies have established that the dynein-interacting proteins Lis1 and dynactin (9)(10)(11) and the centrosomal proteins Cep120 and TACC (12) are required for INM and specifically its bl3ap leg during G2, hence providing evidence for a role of microtubules and minus enddirected motor proteins in this process. Bl3ap INM of APs is thus highly related to nuclear positioning before mitosis, a ubiquitous microtubule-based process that evolved in single-cell eukaryotes (13).…”

A small molecule accelerates neuronal differentiation in the adult rat

“…Our findings suggest that shRNA-or KHS101-mediated interference with TACC3 accelerates neurogenesis through negative regulation of the cell cycle and concomitant activation of a neuronal differentiation program in NPCs. A body of literature suggests that TACC3 is playing a crucial role in progenitor cell maintenance and is down-regulated upon differentiation (23)(24)(25)(26)(27)37), although the molecular mechanisms downstream of TACC3 have yet to be determined. As proposed in a previous study (24), TACC3 may sequester distinct transcription factors to the cytoplasm or to the centrosome, therefore preventing them from binding to transcriptionally active promoters.…”

“…Moreover, previous expression studies of Tacc3 as well as loss-of-function studies in mice, hematopoietic stem cells, and embryonic neural stem cells point to a role for Tacc3 in controlling progenitor cell expansion and terminal differentiation during development (23)(24)(25)(26)(27). Postnatally, TACC3 expression becomes restricted to the remaining proliferative tissues such as spleen, thymus, gastrointestinal (GI) tract, and cerebral areas including the hippocampus (23, 26).…”

Interkinetic Nuclear Movement in the Ventricular Zone of the Cortex

“…The first is Cep120, a centrosomal protein highly expressed in neural progenitors. The second is rather a group of proteins, transforming acidic coiled-coil proteins (TACCs), centrosome-and microtubule-associated proteins that have previously been implicated in microtubule growth and nuclear migration (Xie et al 2007). Cep120 interacts with TACCs and regulates the localization of TACC3 to the centrosome.…”

“…Centrosomes are found at the endfeet of radial glia as cell cycle progresses. Nevertheless, centrosomal integrity and the regulation of microtubules associated with the centrosome are important for proper nuclear oscillation (Xie et al 2007). Furthermore, the asymmetric segregation of the centrioles to the daughter cells affects cell fate.…”