The molecular mechanisms that determine glial cell fate in the vertebrate nervous system have not been elucidated. Peripheral glial cells differentiate from pluripotent neural crest cells. We show here that the transcription factor Sox10 is a key regulator in differentiation of peripheral glial cells. In mice that carry a spontaneous or a targeted mutation of Sox10, neuronal cells form in dorsal root ganglia, but Schwann cells or satellite cells are not generated. At later developmental stages, this lack of peripheral glial cells results in a severe degeneration of sensory and motor neurons. Moreover, we show that Sox10 controls expression of ErbB3 in neural crest cells. ErbB3 encodes a Neuregulin receptor, and down-regulation of ErbB3 accounts for many changes in development of neural crest cells observed in Sox10 mutant mice. Sox10 also has functions not mediated by ErbB3, for instance in the melanocyte lineage. Phenotypes observed in heterozygous mice that carry a targeted Sox10 null allele reproduce those observed in heterozygous Sox10 Dom mice. Haploinsufficiency of Sox10 can thus cause pigmentation and megacolon defects, which are also observed in Sox10 Dom /+ mice and in patients with Waardenburg-Hirschsprung disease caused by heterozygous SOX10 mutations.

Limb muscles develop from cells that migrate from the somites. The signal that induces migration of myogenic precursor cells to the limb emanates from the mesenchyme of the limb bud. Here we report that the c-met-encoded receptor tyrosine kinase is essential for migration of myogenic precursor cells into the limb anlage and for migration into diaphragm and tip of tongue. In c-met homozygous mutant (-/-) mouse embryos, the limb bud and diaphragm are not colonized by myogenic precursor cells and, as a consequence, skeletal muscles of the limb and diaphragm do not form. In contrast, development of the axial skeletal muscles proceeds in the absence of c-met signalling. The specific ligand of the c-met protein, the motility and growth factor scatter factor/hepatocyte growth factor, is expressed in limb mesenchyme and can thus provide the signal for migration which is received by c-met. We have therefore identified a paracrine signalling system that regulates migration of myogenic precursor cells.

In mammals, the transcription factor SRY, encoded by the Y chromosome, is normally responsible for triggering the indifferent gonads to develop as testes rather than ovaries. However, testis differentiation can occur in its absence. Here we demonstrate in the mouse that a single factor, the forkhead transcriptional regulator FOXL2, is required to prevent transdifferentiation of an adult ovary to a testis. Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9. Concordantly, reprogramming of granulosa and theca cell lineages into Sertoli-like and Leydig-like cell lineages occurs with testosterone levels comparable to those of normal XY male littermates. Our results show that maintenance of the ovarian phenotype is an active process throughout life. They might also have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women.

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Sox10 is a high-mobility-group transcriptional regulator in early neural crest. Without Sox10, no glia develop throughout the peripheral nervous system. Here we show that Sox10 is restricted in the central nervous system to myelin-forming oligodendroglia. In Sox10-deficient mice progenitors develop, but terminal differentiation is disrupted. No myelin was generated upon transplantation of Sox10-deficient neural stem cells into wild-type hosts showing the permanent, cell-autonomous nature of the defect. Sox10 directly regulates myelin gene expression in oligodendrocytes, but does not control erbB3 expression as in peripheral glia. Sox10 thus functions in peripheral and central glia at different stages and through different mechanisms.

The nuclear hormone receptor retinoic acid receptor–related orphan receptor γt (RORγt) is required for the generation of T helper 17 cells expressing the proinflammatory cytokine interleukin (IL)-17. In vivo, however, less than half of RORγt+ T cells express IL-17. We report here that RORγt+ Tαβ cells include Foxp3+ cells that coexist with IL-17–producing RORγt+ Tαβ cells in all tissues examined. The Foxp3+ RORγt+ Tαβ express IL-10 and CCL20, and function as regulatory T cells. Furthermore, the ratio of Foxp3+ to IL-17–producing RORγt+ Tαβ cells remains remarkably constant in mice enduring infection and inflammation. This equilibrium is tuned in favor of IL-10 production by Foxp3 and CCL20, and in favor of IL-17 production by IL-6 and IL-23. In the lung and skin, the largest population of RORγt+ T cells express the γδ T cell receptor and produce the highest levels of IL-17 independently of IL-6. Thus, potentially antagonistic proinflammatory IL-17–producing and regulatory Foxp3+ RORγt+ T cells coexist and are tightly controlled, suggesting that a perturbed equilibrium in RORγt+ T cells might lead to decreased immunoreactivity or, in contrast, to pathological inflammation.

Neuregulins and their specific receptors, members of the ErbB family of tyrosine kinases, have been implicated in the control of growth and development of Schwann cells, specialized cells that wrap around nerve axons to provide electrical insulation. Here we use gene targeting to generate mice that lack ErbB3, a high-affinity neuregulin receptor. Homozygous erbB3 mutant embryos lack Schwann-cell precursors and Schwann cells that accompany peripheral axons of sensory and motor neurons. The initial development of motor neurons and sensory neurons of dorsal root ganglia occurs as it should, but at later stages most motor neurons (79%) and sensory neurons in dorsal root ganglia (82%) undergo cell death in erbB3 mutant embryos. Degeneration of the peripheral nervous system in erbB3 mutant pups is thus much more severe than the cell death in mice that lack neurotrophins or neurotrophin receptors. We also show that ErbB3 functions in a cell-autonomous way during the development of Schwann cells, but not in the survival of sensory or motor neurons. Our results indicate that sensory and motor neurons require factors for their survival that are provided by developing Schwann cells.

The neuronal networks that generate vertebrate movements such as walking and swimming are embedded in the spinal cord [1][2][3] . These networks, which are referred to as central pattern generators (CPGs), are ideal systems for determining how ensembles of neurons generate simple behavioural outputs. In spite of efforts to address the organization of the locomotor CPG in walking animals 2,4-6 , little is known about the identity and function of the spinal interneuron cell types that contribute to these locomotor networks. Here we use four complementary genetic approaches to directly address the function of mouse V1 neurons, a class of local circuit inhibitory interneurons that selectively express the transcription factor Engrailed1. Our results show that V1 neurons shape motor outputs during locomotion and are required for generating 'fast' motor bursting. These findings outline an important role for inhibition in regulating the frequency of the locomotor CPG rhythm, and also suggest that V1 neurons may have an evolutionarily conserved role in controlling the speed of vertebrate locomotor movements.Several genetically defined classes of neurons have been identified in the developing spinal cord 7 , including a class of ipsilaterally projecting inhibitory neurons that innervate motor neurons, the Engrailed1 (En1)-expressing V1 neurons [8][9][10][11] . To assess the function of V1 neurons in the locomotor CPG, we used two mouse models that have selective loss of the En1-expressing V1 neuronal population (Fig. 1). This was achieved through the altered specification of V1 neurons in Pax6-knockout (Pax6 2/2 ) mice and by the selective ablation of these neurons in En1Cre ; R26-lacZ flox /DTA (En1-DTA; ref. 12) mice. At embryonic day (E)12.5, a marked reduction in En1-positive V1 neuron cell numbers was apparent in spinal cords isolated from Pax6 2/2 and En1-DTA embryos (Fig. 1a, e). This was confirmed using an En1Cre lacZ or green fluorescent protein (GFP) reporter system 9 , which also showed that significantly fewer En1-derived V1 neurons are present at E18.5 (Fig. 1b, f). Both Pax6 2/2 and En1-DTA mice had normal numbers of lumbar spinal motor neurons that were appropriately organized into lateral and medial motor columns. (Fig. 1c, g). Spinal cords from Pax6 2/2 mice did show an increase in commissural V0 and V3 interneuron cell numbers, coupled with a slight decrease in ipsilaterally projecting Chx10-positive V2 neurons 13 (Chx10 is a marker of V2 neurons; Supplementary Fig. S1). However, there were no changes in ventral