From CNS stem cells to neurons and glia: Sox for everyone

Abstract

Neuroepithelial precursor cells of the vertebrate central nervous system either self-renew or differentiate into neurons, oligodendrocytes or astrocytes under the influence of a gene regulatory network that consists in transcription factors, epigenetic modifiers and microRNAs. Sox transcription factors are central to this regulatory network, especially members of the SoxB, SoxC, SoxD, SoxE and SoxF groups. These Sox proteins are widely expressed in neuroepithelial precursor cells and in newly specified, differentiating and mature neurons, oligodendrocytes and astrocytes and influence their identity, survival and development. They exert their effect predominantly at the transcriptional level but also have substantial impact on expression at the epigenetic and posttranscriptional levels with some Sox proteins acting as pioneer factors, recruiting chromatin-modifying and -remodelling complexes or influencing microRNA expression. They interact with a large variety of other transcription factors and influence the expression of regulatory molecules and effector genes in a cell-type-specific and temporally controlled manner. As versatile regulators with context-dependent functions, they are not only indispensable for central nervous system development but might also be instrumental for the development of reprogramming and cell conversion strategies for replacement therapies and for assisted regeneration after injury or degeneration-induced cell loss in the central nervous system.

C. elegansSoxB genes are dispensable for embryonic neurogenesis but required for terminal differentiation of specific neuron types

“…SoxB genes have been associated with broad neurogenic functions throughout the animal kingdom, from deuterostomes (chordates, echinoderms, hemichordates) (Burke et al, 2014;Reiprich and Wegner, 2014;Taguchi et al, 2002) and protostomes (Ecdysozoa, Lophotrochozoa) (Kerner et al, 2009;Overton et al, 2002) to even earlier diverging animal lineages such as cnidarians (Richards and Rentzsch, 2014). SoxB proteins are required for neuronal commitment broadly throughout the embryonic nervous system during the earliest stages of development, predominantly in proliferating, undifferentiated precursors (Pevny and Placzek, 2005;Pevny and Nicolis, 2010;Reiprich and Wegner, 2014;Sarkar and Hochedlinger, 2013).…”

“…As a complementary approach to understand nervous system development we set out to identify factors involved in early neurogenesis in C. elegans ('top-down approach'). Given the roles of SoxB and SoxC genes in early neurogenesis in various species (Reiprich and Wegner, 2014), we examined the expression of the C. elegans SoxB1 gene sox-2, the SoxB2 gene sox-3 and the SoxC gene sem-2 using fosmid-based reporter genes (Fig. 1).…”

“…Sox proteins fall into eight main groups based on sequence identity and have been implicated in various developmental processes, with members of the same group often showing functional redundancy (Table 1) (Guth and Wegner, 2008). Members of the SoxB and SoxC groups are important regulators of different steps of nervous system development in diverse species (Reiprich and Wegner, 2014). …”

“…Mammalian SoxB1 genes are important to establish neuroectodermal fate and are key regulators of neural stem cell maintenance during development and in adult neurogenic regions (Pevny and Placzek, 2005;Reiprich and Wegner, 2014). Furthermore, the mammalian Sox2 gene is a key pluripotency factor (Takahashi and Yamanaka, 2006).…”

Deciphering the core instructions of neuronal differentiation

“…The recognition of Sox protein binding to a large numbers of genes involved in these functions provides major progress (Reiprich and Wegner 2014;Ernsberger 2014, this issue). SoxB and SoxC protein binding in chromatin environments reflecting different transcriptional activity states in stem cells, progenitors and differentiated neurons points to the importance of histone modification for transcriptional regulation during developmental realization of the differentiated state.…”