The Sox9 transcription factor determines glial fate choice in the developing spinal cord.
Journal: 2003/July - Genes and Development
ISSN: 0890-9369
Abstract:
The mechanism that causes neural stem cells in the central nervous system to switch from neurogenesis to gliogenesis is poorly understood. Here we analyzed spinal cord development of mice in which the transcription factor Sox9 was specifically ablated from neural stem cells by the CRE/loxP recombination system. These mice exhibit defects in the specification of oligodendrocytes and astrocytes, the two main types of glial cells in the central nervous system. Accompanying an early dramatic reduction in progenitors of the myelin-forming oligodendrocytes, there was a transient increase in motoneurons. Oligodendrocyte progenitor numbers recovered at later stages of development, probably owing to compensatory actions of the related Sox10 and Sox8, both of which overlap with Sox9 in the oligodendrocyte lineage. In agreement, compound loss of Sox9 and Sox10 led to a further decrease in oligodendrocyte progenitors. Astrocyte numbers were also severely reduced in the absence of Sox9 and did not recover at later stages of spinal cord development. Taking the common origin of motoneurons and oligodendrocytes as well as V2 interneurons and some astrocytes into account, stem cells apparently fail to switch from neurogenesis to gliogenesis in at least two domains of the ventricular zone, indicating that Sox9 is a major molecular component of the neuron-glia switch in the developing spinal cord.
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Genes Dev 17(13): 1677-1689

The Sox9 transcription factor determines glial fate choice in the developing spinal cord

Institut für Biochemie, Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
INSERM U470, Institute de Biochimie, Université Nice, 06108 Nice cedex 2, France
E-MAIL ed.negnalre-inu.mehcoib@rengew.m; FAX 49 9131 85 22484.
Received 2003 Jan 8; Accepted 2003 May 5.

Abstract

The mechanism that causes neural stem cells in the central nervous system to switch from neurogenesis to gliogenesis is poorly understood. Here we analyzed spinal cord development of mice in which the transcription factor Sox9 was specifically ablated from neural stem cells by the CRE/loxP recombination system. These mice exhibit defects in the specification of oligodendrocytes and astrocytes, the two main types of glial cells in the central nervous system. Accompanying an early dramatic reduction in progenitors of the myelin-forming oligodendrocytes, there was a transient increase in motoneurons. Oligodendrocyte progenitor numbers recovered at later stages of development, probably owing to compensatory actions of the related Sox10 and Sox8, both of which overlap with Sox9 in the oligodendrocyte lineage. In agreement, compound loss of Sox9 and Sox10 led to a further decrease in oligodendrocyte progenitors. Astrocyte numbers were also severely reduced in the absence of Sox9 and did not recover at later stages of spinal cord development. Taking the common origin of motoneurons and oligodendrocytes as well as V2 interneurons and some astrocytes into account, stem cells apparently fail to switch from neurogenesis to gliogenesis in at least two domains of the ventricular zone, indicating that Sox9 is a major molecular component of the neuron–glia switch in the developing spinal cord.

Keywords: HMG-box, Sry, Sox10, neural stem cell, oligodendrocyte, astrocyte
Abstract

Neuronal specification has been intensely studied in the spinal cord (for review, see Jessell 2000). Neuronal subtypes are generated in response to a Sonic hedgehog gradient that emanates from notochord and floorplate, and influences the expression of transcription factors along the dorsoventral axis. Some of these transcription factors are repressed (class I) by Sonic hedgehog, and others are induced (class II). Because of the cross-repressive action of these transcription factors, domains are established in the ventricular zone along the dorsoventral axis, with each domain defined by expression of a certain set of transcription factors and giving rise to a particular type of neuron. Thus, motoneurons arise from the pMN domain in the ventral part of the ventricular zone, whereas V2 interneurons are generated from the dorsally abutting p2 domain.

Although neuronal specification and its underlying molecular principles are well understood, relatively little is known about the origin of glia in the spinal cord (for review, see Kessaris et al. 2001). Stem cells within the ventricular zone cease to produce neurons at around midgestation and instead start to produce glia. What causes these stem cells to switch from neurogenesis to gliogenesis is unknown at present.

Myelin-forming oligodendrocytes and nonmyelinating astrocytes are the two main types of glia in the central nervous system (CNS). They appear to arise from different regions of the ventricular zone, with oligodendrocytes being derived from the same pMN domain that gave rise to motoneurons before. Generation of both motoneurons and oligodendrocytes is dependent on the action of the Olig1/2 transcription factors of the bHLH family (Lu et al. 2002; Takebayashi et al. 2002; Zhou and Anderson 2002). The origin of astrocytes within the ventricular zone is less well defined. Recent studies have shown, however, that the p2 domain is capable of astrocyte production (Zhou and Anderson 2002; Pringle et al. 2003). Additionally, astrocytes appear to be generated by transdifferentiation of radial glia (Bignami and Dahl 1974; Malatesta et al. 2003), pointing to a heterogeneous origin of astrocytes.

We have shown that glial cells of the CNS express proteins of the Sox family of transcription factors (Kuhlbrodt et al. 1998a,b; Sock et al. 2001). Sox proteins in general are characterized by possession of a variant high-mobility-group domain that allows sequence-specific minor-groove DNA binding and concomitant DNA bending. Sox proteins can be grouped into seven major classes and have important roles during development (Wegner 1999; Bowles et al. 2000). The class E protein Sox10, for instance, is essential for development of several neural-crest-derived cell types, including all peripheral glia (Herbarth et al. 1998; Southard-Smith et al. 1998; Britsch et al. 2001). In the CNS, Sox10 occurs selectively in oligodendrocytes and is essential for the terminal differentiation of these cells (Stolt et al. 2002). Sox10 expression in the oligodendrocyte lineage significantly precedes the onset of terminal differentiation, but is apparently not essential during these earlier times.

In addition to Sox10, oligodendrocytes also express the related Sox8 protein (Sock et al. 2001). Coexpression of Sox8 and Sox10 is observed both in developing and terminally differentiated oligodendrocytes with little changes in the relative levels of both transcription factors during lineage progression. This and normal oligodendrocyte development in Sox8-deficient mice (Sock et al. 2001; C.C. Stolt and M. Wegner, unpubl.) make it unlikely that functional compensation by Sox8 is the main reason for the absence of an early oligodendrocyte defect in Sox10-deficient mice.

The second protein closely related to Sox10 is Sox9, which is best known for its role during chondrocyte development and male sex determination (Wright et al. 1995; Kent et al. 1996; Bi et al. 1999). Heterozygous mutations in humans lead to campomelic dysplasia (MIM 114290), a skeletal malformation syndrome frequently associated in males with XY sex reversal (Foster et al. 1994; Wagner et al. 1994). Poorly characterized defects in the CNS are, however, additionally observed in campomelic dysplasia patients, indicating that there might be an additional role of Sox9 in the CNS.

Here, we show that Sox9 is strongly expressed first in neural stem cells, and later in glial cells of the CNS, and that it is essential for proper development of both oligodendrocytes and astrocytes. Not only do our findings explain the previously noted absence of an early oligodendrocyte defect in Sox10-deficient mice, it also defines Sox9 as a component of the mechanism that causes neural stem cells to switch from neurogenesis to gliogenesis.

Acknowledgments

We thank J. Briscoe, C. Birchmeier, T. Müller, H. Takebayashi, and W. Stallcup for the gift of antibodies, W.D. Richardson and M. Sander for in situ probes, and G. Schütz for the Nestin-Cre mice. This study was supported by grant We1326/7-2 from the DFGto M.W.

The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 USC section 1734 solely to indicate this fact.

Acknowledgments

Notes

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.259003.

Corresponding author.

Notes
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.259003.
Corresponding author.
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