Spatial and temporal specification of neural fates by transcription factor codes

Abstract

The vertebrate central nervous system contains a great diversity of neurons and glial cells, which are generated in the embryonic neural tube at specific times and positions. Several classes of transcription factors have been shown to control various steps in the differentiation of progenitor cells in the neural tube and to determine the identity of the cells produced. Recent evidence indicates that combinations of transcription factors of the homeodomain and basic helix-loop-helix families establish molecular codes that determine both where and when the different kinds of neurons and glial cells are generated. IntroductionA multitude of neurons of different types, as well as oligodendrocytes and astrocytes (see Box 1), are generated as the vertebrate central nervous system develops. These different neural cells are generated at defined times and positions by multipotent progenitors located in the walls of the embryonic neural tube. Progenitors located in the ventral neural tube at spinal cord level first produce motor neurons, which innervate skeletal muscles and later produce oligodendrocytes (Fig. 1). The first cells produced by progenitors at more dorsal or ventral positions in the spinal cord are interneurons of different classes. The generation of a particular class of neuron or glial cell from a multipotent progenitor is a complex process that can be subdivided into a series of sequential steps ( Fig. 2A,B). First, progenitor cells acquire unique positional identities through a process of spatial patterning of the neural primordium. Thus, progenitors in the ventral spinal cord that produce motor neurons and oligodendrocytes acquire a distinct identity from that of progenitors in the dorsal spinal cord or brain. Multipotent progenitors then produce daughter progenitor cells that are restricted to produce only one of the primary neural cell types -neurons, oligodendrocytes or astrocytes -in a step called cell type selection or commitment. Committed neuronal progenitors also become specified to produce neurons of a particular kind, e.g. a particular class of motor neuron or interneuron, a step called subtype specification that is conceptually distinct from, but mechanistically tightly linked to, the step of cell type commitment, as we will see. Neuronal progenitors then stop dividing, migrate out of the progenitor zones they occupy (see Fig. 1B) and towards more differentiated areas of the neural tube. There they initiate a programme of terminal differentiation. Oligodendrocytes, astrocytes and some types of neurons begin to migrate and differentiate while still dividing.The fact that particular classes of neurons and glial cells are produced only at particular locations in the embryonic neural tube suggests that the mechanisms that govern spatial patterning and the acquisition of diverse cell fates are linked. Moreover, neurons and glial cells are produced in a defined order (first neurons, then oligodendrocytes, then astrocytes), and different classes of neurons originating from the same progenitors are al...

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“…During neurogenesis, the progenitor cells that become committed to a neuronal fate express TFs of the basic helix-loop-helix (bHLH) family, known as proneural genes (31). In the mouse hypothalamus, it has been shown that the proneural genes Ascl1 and Ngn3 are necessary for hypothalamic neurogenesis and, more specifically, Ascl1 −/− as well as Ngn3 −/− mutant mice have a reduced number of hypothalamic POMC neurons (32,33).…”

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“…During development, progenitor cells in the nervous system express combinatorial codes of transcriptional factors that initiate a cascade of cell fate specification [23]. These transcription factors regulate expression of target genes involved in cell migration, connectivity, and signaling.…”

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“…Proneural bHLH genes can also direct the formation of specific neuronal cell types, as exemplified by studies in the vertebrate spinal cord (Sugimori et al, 2007) and retina (Hatakeyama and Kageyama, 2004). Neuronal cell type specification is commonly due to the combinatorial action of proneural and homeodomain-containing proteins (Guillemot, 2007). We demonstrate here that three transcription factors: the L(1)sc bHLH protein (Alonso and Cabrera, 1988), Tailup (Tup; Islet) Limhomeodomain protein (Thor and Thomas, 1997) and the Sox family protein SoxNeuro (SoxN) (Buescher et al, 2002;Cremazy et al, 2000;Overton et al, 2002), work together to control overlapping aspects of H-cell gene expression.…”