The molecular mechanisms mediating neural fate decisions in the developing forebrain

Abstract

During cerebral cortical development, excitatory glutamatergic projection neurons are generated from neural stem cells (NSCs) intrinsic to the early embryonic cortical ventricular zone, whereas most inhibitory GABAergic interneurons and oligodendrocytes (OLs) are elaborated from ventral forebrain stem cells that initially undergo tangential cortical migration to the cerebral cortical plate prior to lineage maturation. Therefore, the generation of neurons and OLs from a common ventral forebrain progenitor cell would expose these cells to the sequential actions of ventral and dorsal gradient morphogens (sonic hedgehog, Shh and bone morphogenetic proteins, BMPs respectively) that normally mediate opposing developmental programs. In the first chapter of this thesis, we report that Shh promotes GABAergic neuronal/OL lineage restriction of multipotent NSCs, in part, by activating the expression of the basic helix-loop-helix (bHLH) transcription factors, Olig2 and Mash1. Furthermore, the sequential elaboration of cortical GABAergic neurons and OLs from common Shh-responsive ventral forebrain progenitors requires the spatial and temporal modulation of cortical BMP signaling by BMP ligands and the BMP antagonist, noggin, respectively. The second chapter of this thesis further demonstrates that Olig2 is crucial for the coupling of GABAergic neuronal progenitors to OL precursors, OL lineage maturation, and lineage-restricted neuronal/OL progenitor cell proliferation in the ventral forebrain. In addition, Olig2 expression is necessary for preserving the integrity of specific ventral forebrain progenitor domains and promotes the elaboration of the parvalbumin-expressing subtype of cortical GABAergic neurons and OLs while actively suppressing the alternate elaboration of cholinergic neurons and astrocytes. Finally, the third chapter of this thesis demonstrates that an Olig2-related bHLH transcription factor, Olig1, is necessary for OL lineage commitment, OL lineage maturation, the coupling of OL progenitor cell cycle exit to terminal OL differentiation and for latter stages of axonal myelination. In addition, this study reveals that Olig2 has a partially overlapping spectrum of developmental actions in common with Olig1 as deficits in OL specification and lineage maturation found in the Olig1 null mutants can be fully compensated by overexpression Olig1 but not Olig2 using the respective Olig-expressing viral vectors.