Tumor suppressor Nf2 limits expansion of the neural progenitor pool by inhibiting Yap/Taz transcriptional coactivators

Abstract

SUMMARYBrain development requires a precise balance between expansion of the neural progenitor pool and the production of postmitotic neurons and glia. Disruption of this equilibrium results in a myriad of structural abnormalities and disorders of the nervous system. The molecular mechanism that restricts neural progenitor expansion is poorly understood. Here we show that the tumor suppressor neurofibromatosis 2 (Nf2; merlin) limits the expansion of neural progenitor cells (NPCs) in the mammalian dorsal telencephalon. Nf2 is localized at the apical region of NPCs. In the absence of Nf2, NPCs of the cortical hem, hippocampal primordium and neocortical primordium overexpand, while production of Cajal-Retzius cells and hippocampal neurons decreases, resulting in severe malformation of the hippocampus in adult mice. We further show that Nf2 functions by inhibiting the Yap/Taz transcriptional coactivators, probably through a mechanism that is distinct from the canonical Hippo pathway. Overexpressing human YAP in NPCs causes a hippocampal malformation phenotype that closely resembles that of Nf2 mutants and, importantly, deleting Yap in the Nf2 mutant background largely restores hippocampal development. Our studies uncover Nf2 as an important inhibitor of neural progenitor expansion and establish Yap/Taz as key downstream effectors of Nf2 during brain development.

The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap

“…We examined Nf2 protein localization at E15.5, when pioneer axons reach the midline. As reported previously (Lavado et al, 2013), Nf2 localized at the apical region of NPCs, highlighting the ventricular surface (Fig. 1G, arrowhead).…”

“…We previously found that deleting floxed alleles of Nf2 (Nf2 (Giovannini et al, 2000) with Emx1-cre, which is expressed in the dorsal telencephalon by E10.5 (Gorski et al, 2002), results in callosal agenesis (Lavado et al, 2013). Luxol Blue staining of adult brain sections to detect myelinated axons showed that, in Nf2 mutants (Nf2 F/F ;Emx1-Cre), the corpus callosum was absent along the rostrocaudal axis with few, if any, fibers crossing the midline (Fig.…”

“…Using Nf2 conditional knockout mouse models, we have previously shown that Nf2 limits the expansion of neural progenitor cell (NPC) populations during brain development by inhibiting the transcriptional coactivators Yap (Yap1 -Mouse Genome Informatics) and its paralog Taz (here referred to as Yap/ Taz) (Lavado et al, 2013). Nf2 loss and YAP hyperactivation also render the dentate gyrus radial glial scaffold over-exuberant and impair hippocampus morphogenesis.…”

YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation

“…Our results are consistent with these previous studies. We are also aware of reports that YAP regulates neural progenitor cell numbers in the developing neural tube of chick and Xenopus embryos and the mouse hippocampus, as shown in YAP gain-or loss-of-function assays (Cao et al, 2008;Gee et al, 2011;Lavado et al, 2013;Piccolo et al, 2014). However, our results showed normal neocortical neurogenesis in culture and in P0-P1 Yap nestin -CKO mice (Figs 3, 5, 6 and S6).…”

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

“…Knockdown of FAT4 in the developing chick or mouse neural tube increases neural progenitor numbers in a YAP-dependent fashion (Cappello et al, 2013;Van Hateren et al, 2011). Additionally, NF2/Merlin has recently been shown to suppress mouse neural progenitor expansion by inhibiting TAZ/YAP activity (Lavado et al, 2013). How nuclear TAZ/YAP activity controls progenitor proliferation is poorly understood, but is likely to involve the activation of genes encoding cell cycle regulators, such as cyclin D1, and inhibition of pro-differentiation factors, such as NeuroM (Cao et al, 2008).…”