Molecular control of neurogenesis: a view from the mammalian cerebral cortex

Abstract

The mammalian nervous system is the most complex organ of any living organism. How this complexity is generated during neural development is just beginning to be elucidated. This article discusses the signaling, transcriptional, and epigenetic mechanisms that are involved in neural development. The first part focuses on molecules that control neuronal numbers through regulation of the timing of onset of neurogenesis, the timing of the neuronal-to-glial switch, and the rate of progenitor proliferation. The second part focuses on molecules that control neuronal diversity by generating spatially or temporally distinct populations of neuronal progenitors. Most of the studies discussed in this article are focused on the developing mammalian cerebral cortex, because this is one of the main model systems for neural developmental studies and many of the mechanisms identified in this tissue also operate elsewhere in the developing brain and spinal cord.

Figure 1.

Molecular pathways regulating the onset, progression, and termination of neurogenesis in the rodent cerebral cortex. The onset of neurogenesis is concomitant with the transformation of neuroepithelial stem cells (A) into radial glial (RG) stem cells (C). Several signaling pathways, including the Dll1/Notch, Nrg1/ErB, and Fgf10/Fgfr2 pathways have been implicated in this transformation (see text). RG cells then generate neurons directly (D) or via basal progenitors (E). Several transcription factors (Ap2γ, Ngn2, Insm1, Tbr2) have been shown to promote the generation of basal progenitors from RGs, whereas the Notch and FGF pathways and the epigenetic regulator Ezh2 inhibit this step. Whether AP2γ, Ngn2, and Insm1 act primarily by inducing Tbr2 expression or also via Tbr2-independent mechanisms is unclear. Other transcription factors and signaling molecules promote the self-renewal of RGs (Wnt, Myc) and the proliferation of basal progenitors (Foxg1, Wnt/n-Myc). Whether the same factors and pathways that promote the direct generation of neurons by RGs (Pax6, Ngn1/2, RA) also drive the generation of neurons by basal progenitors (data not shown) is unclear. The termination of neurogenesis results from the terminal differentiation of RGs into astrocytes (G). Multiple signaling pathways (Jack/Stat, Notch, BMP, FGF) synergize to elicit the neurogenic-to-gliogenic switch (see text). It is noteworthy that the same pathways frequently operate in different temporal contexts to exert contrasting cellular effects.

Figure 2.

Spatial mechanisms of neuronal fate specification. (A) BMP and Wnt signals, diffusing from the dorsal midline of the telencephalon, induce expression of important transcriptional regulators of dorsal telencephalic fates (Emx1/2, Pax6, Ngn1/2). Pax6 and Ngn1/2 promote neurogenesis and specify the glutamatergic projection neuron identity of neurons born in the cerebral cortex. (B) The morphogen Shh secreted by the ventral midline of the telencephalon, represses the activity of Gli3 and induces the expression of transcriptional determinants of ventral telencephalic cell fates, including Nkx2.1 and Gsh1/2. Gsh1/2 induce expression of the pro-neural gene Ascl1, which together with its targets Dlx1/2 promotes neurogenesis and contributes to the specification of GABAergic neurons, including basal ganglial neurons and cortical interneurons, in the ventral telencephalon. Nkx2.1, through induction of Lhx6 and Sox6, further specifies subpopulations of cortical interneurons defined by the expression of the calcium-binding protein parvalbumin and the peptide somatostatin. (C) Dorsally or ventrally restricted expression of transcriptional determinants of neuronal fates. The sharp boundary of their expression domains is established by cross-repression (shown in A and B).

Figure 3.

Temporal mechanisms of neuronal fate specification. (A) Distinct neuronal subtypes are generated sequentially in an inside-first–outside-last order during neurogenesis, by progenitors located in the cortical ventricular zone (VZ) and subventricular zone (SVZ), resulting in the layered organization of the adult cerebral cortex. The intermediate zone (IZ), subplate (SP), and marginal zone (MZ) are present only transiently in the embryonic cortex. (B) Cortical projection (CP) neurons are generated either directly from radial glial stem cells or indirectly via intermediate basal progenitors (BPs). (C) The transcription factors that specify the identity of the distinct classes of projection neurons forming the different cortical layers (see Molyneaux et al. 2007). (D) Transcription factors that specify cortical neuron identities are involved in cross-repressive interactions whereby a layer-specific determinant represses directly (solid lines) or indirectly (dashed lines) the transcription factors involved in neuronal specification in neighboring layers. Abbreviations: VI, layer VI; V, layer V; IV, layer IV; I/II/III, layers I, II, and III.