Sox proteins are characterized by possession of a DNA-binding domain with similarity to the high-mobility group domain of the sex determining factor SRY. Here, we report on Sox10, a novel protein with predominant expression in glial cells of the nervous system. During development Sox10 first appeared in the forming neural crest and continued to be expressed as these cells contributed to the forming PNS and finally differentiated into Schwann cells. In the CNS, Sox10 transcripts were originally confined to glial precursors and later detected in oligodendrocytes of the adult brain. Functional studies failed to reveal autonomous transcriptional activity for Sox10. Instead, Sox10 functioned synergistically with the POU domain protein Tst-1/Oct6/SCIP with which it is coexpressed during certain stages of Schwann cell development. Synergy depended on binding to adjacent sites in target promoters, was mediated by the N-terminal regions of both proteins, and could not be observed between Sox10 and several other POU domain proteins. Interestingly, Sox10 also modulated the function of Pax3 and Krox-20, two other transcription factors involved in Schwann cell development. We propose a role for Sox10 in conferring cell specificity to the function of other transcription factors in developing and mature glia.

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.

The myelin-forming oligodendrocytes are an excellent model to study transcriptional regulation of specification events, lineage progression, and terminal differentiation in the central nervous system. Here, we show that the group D Sox transcription factors Sox5 and Sox6 jointly and cell-autonomously regulate several stages of oligodendrocyte development in the mouse spinal cord. They repress specification and terminal differentiation and influence migration patterns. As a consequence, oligodendrocyte precursors and terminally differentiating oligodendrocytes appear precociously in spinal cords deficient for both Sox proteins. Sox5 and Sox6 have opposite functions than the group E Sox proteins Sox9 and Sox10, which promote oligodendrocyte specification and terminal differentiation. Both genetic as well as molecular evidence suggests that Sox5 and Sox6 directly interfere with the function of group E Sox proteins. Our studies reveal a complex regulatory network between different groups of Sox proteins that is essential for proper progression of oligodendrocyte development.

The high-mobility-group domain-containing transcription factor Sox11 is expressed transiently during embryonic development in many tissues that undergo inductive remodeling. Here we have analyzed the function of Sox11 by gene deletion in the mouse. Sox11-deficient mice died at birth from congenital cyanosis, likely resulting from heart defects. These included ventricular septation defects and outflow tract malformations that ranged from arterial common trunk to a condition known as double outlet right ventricle. Many other organs that normally express Sox11 also exhibited severe developmental defects. We observed various craniofacial and skeletal malformations, asplenia, and hypoplasia of the lung, stomach, and pancreas. Eyelids and the abdominal wall did not close properly in some Sox11-deficient mice. This phenotype suggests a prime function for Sox11 in tissue remodeling and identifies SOX11 as a potentially mutated gene in corresponding human malformation syndromes.Transcription factors of the Sox protein family are characterized by the possession of a subtype of high-mobility-group domain which allows sequence-specific binding to the minor groove of DNA (31). This domain was first identified in Sry, the prototypic family member involved in male sex determination. Over the last few years, many Sox proteins have been shown to be involved as regulators in diverse developmental processes ranging from epiblast formation to the terminal differentiation of certain cell types (3, 31).The 20 Sox proteins which have been identified in mammals can be further subdivided into eight groups (groups A to H) according to their degrees of similarity both within and outside the high-mobility-group domain. Mammalian group C, for instance, consists of the three highly related proteins Sox4, Sox11, and Sox22. Sox4 has been studied extensively in vivo and has been shown to be essential for pro-B-cell expansion and for the formation of semilunar valves and of the outflow tract from the endocardial ridges of the heart (25). Further nonessential roles for Sox4 have been defined in thymocyte differentiation (24).Much less is known about the biological role of Sox11 and Sox22. Species in which Sox11 has been identified include humans, mice, rats, chickens, Xenopus laevis, and zebra fish (11,14,15,17,21,22,30). Sox11 functions as a strong transcriptional activator in tissue culture systems and possesses a transactivation domain at its extreme carboxy terminus with a high level of homology to the corresponding region of Sox4 (17).The expression of Sox11 has also been studied in several species. In zebra fish, in which two Sox11 orthologs exist because of the recent whole-genome duplication in teleosts, Sox11 transcripts are maternally inherited (22). In all species analyzed, Sox11 is present during gastrulation and early postgastrulation development throughout the embryo, with the notable exception of the heart (14,17,22). Later during development, Sox11 is prominently expressed in the developing nervous system in both glial and neurona...

Glial cells of the oligodendrocyte lineage express several highly related POU proteins including Tst-1/Oct6/ SCIP and Brn-1. Tst-1/Oct6/SCIP, but not Brn-1 efficiently cooperated with Sox10, the only SRY box protein so far identified in oligodendrocytes. Here we show that, in addition to Sox10, cells of the oligodendrocyte lineage contain significant amounts of the related SRY box proteins Sox4 and Sox11. During development, Sox11 was strongly expressed in the central nervous system. It was first detected in neural precursors throughout the neuroepithelium. During later stages of neural development, Sox11 was additionally expressed in areas of the brain in which neurons undergo differentiation. In agreement with its expression in neural precursors, Sox11 levels in cells of the oligodendrocyte lineage were high in precursors and down-regulated during terminal differentiation. Outside the nervous system, expression of Sox11 was also detected in the developing limbs, face, and kidneys. Structure function analysis revealed that Sox11 has a strong intrinsic transactivation capacity which is mediated by a transactivation domain in its carboxyl-terminal part. In addition, Sox11 efficiently synergized with Brn-1. Synergy was dependent on binding of both proteins to adjacent DNA elements, and required the presence of the respective transactivation domain in each protein. Our data suggest the existence of a specific code in which POU proteins require specific Sox proteins to exhibit cooperative effects in glial cells.