Hippo signalling in mammalian cortical development

Abstract

The cerebral cortex in humans is composed of billions of morphologically and functionally distinct neurons. Development of the neocortex requires an orchestrated succession of a series of processes, the appropriate generation, migration, and positioning of neurons, the acquisition of layer-specific transcriptional hallmarks, and the establishment of precise axonal projections. We have primarily focussed on elucidating the transcriptomic landscape of murine embryonic neural stem cells (NSCs), basal progenitors (BPs) and newborn neurons (NBNs) at the population level. I have focussed on one underexplored signalling pathway in the brain- the Hippo signalling pathway. Hippo signalling effectors are expressed dynamically during the course of development in NSCs and BPs at mRNA level. Hippo transcription factors (TFs), Tead1 and Tead3 show higher expression during gliogenesis while Tead2 is expressed at relatively higher levels during early phases of neural expansion. Known to be redundant in other biological systems, I explored different effects of three Tead TFs in NSCs using gain and loss of function. I observe reciprocal effects on neuronal migration and fate with Tead1, Tead3 and Tead2. We identified ApoE, Cyr61 and Dab2 as potential direct targets of Tead TFs in NSCs. ApoE gain of function partially recapitulates the gain of function of Tead2, reducing cell migration to the cortical plate (CP) and Dab2 gain of function recapitulates the gain of function of Tead1, an increased migration to CP. ApoE and Dab2 are involved in Reelin signalling and hence we provide the first link between Hippo and Reelin signalling pathways controlling cortical development.