The Structural and Functional Integrity of Peripheral Nerves Depends on the Glial-Derived Signal Desert Hedgehog

Sharghi-Namini, Soheila; Turmaine, Mark; Meier, Carola; Sahni, Vishal; Umehara, Fujio; Jessen, Kristján R.; Mirsky, Rhona

doi:10.1523/jneurosci.0157-06.2006

Cited by 81 publications

(74 citation statements)

References 65 publications

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“…Alterations in perineurium-derived signals cause defects in myelinating as well as non-myelinating Schwann cells. They lead to an abnormal permeability of the blood-nerve barrier and elevated levels of immune cells in the nerve (Sharghi-Namini et al, 2006). Similar consequences have also been observed in humans in which Dhh loss leads to a peripheral neuropathy with mini-fascicle formation and gonadal dysgenesis (Umehara et al, 2000).…”

Section: Resultssupporting

confidence: 52%

Desert Hedgehog Links Transcription Factor Sox10 to Perineurial Development

Küspert

Weider²,

Müller³

et al. 2012

J. Neurosci.

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Schwann cells are the main glial cell type in the PNS. They develop along nerves during embryogenesis and rely on the HMG domain containing Sox10 transcription factor for specification, lineage progression, and terminal differentiation. Sox10 deletion in immature Schwann cells caused peripheral nerve defects in mice that were not restricted to this glial cell type, although expression in the nerve and gene loss were. Formation of the perineurium as the protecting sheath was, for instance, heavily compromised. This resembled the defect observed after loss of Desert hedgehog (Dhh) in mice. Here we show that Sox10 activates Dhh expression in Schwann cells via an enhancer that is located in intron 1 of the Dhh gene. Sox10 binds this enhancer in monomeric form via several sites. Mutation of these sites abolishes both Schwann-cell-specific activity and Sox10 responsiveness in vitro and in transgenic mouse embryos. This argues that Sox10 activates Dhh expression by direct binding to the enhancer and by increasing Dhh levels promotes formation of the perineurial sheath. This represents the first mechanism for a non-cell-autonomous function of Sox10 during peripheral nerve development.

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Section: Resultssupporting

confidence: 52%

Desert Hedgehog Links Transcription Factor Sox10 to Perineurial Development

Küspert

Weider²,

Müller³

et al. 2012

J. Neurosci.

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show abstract

“…A similar increased number of incisures was observed in mutant mice with altered Schwann cell-axon interactions, including myelin basic protein-deficient shiverer mice (Gould et al, 1995), sulfatide-deficient mice (Hoshi et al, 2007), and desert hedgehog-null mice (Sharghi-Namini et al, 2006). In contrast to desert hedgehog-null mice, both shiverer (Sharghi-Namini et al, 2006) and schwannomin mutant mice displayed an increase in ␤-catenin and NF155 levels, indicating that these various mutations altered SLI numbers through different mechanisms.…”

Section: Discussionmentioning

confidence: 55%

Tumor Suppressor Schwannomin/Merlin Is Critical for the Organization of Schwann Cell Contacts in Peripheral Nerves

Denisenko¹,

Cifuentes‐Diaz²,

Irinopoulou³

et al. 2008

J. Neurosci.

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Schwannomin/merlin is the product of a tumor suppressor gene mutated in neurofibromatosis type 2 (NF2). Although the consequences of NF2 mutations on Schwann cell proliferation are well established, the physiological role of schwannomin in differentiated cells is not known. To unravel this role, we studied peripheral nerves in mice overexpressing in Schwann cells schwannomin with a deletion occurring in NF2 patients (P0 -SCH-⌬39 -121) or a C-terminal deletion. The myelin sheath and nodes of Ranvier were essentially preserved in both lines. In contrast, the ultrastructural and molecular organization of contacts between Schwann cells and axons in paranodal and juxtaparanodal regions were altered, with irregular juxtaposition of normal and abnormal areas of contact. Similar but more severe alterations were observed in mice with conditional deletion of the Nf2 gene in Schwann cells. The number of SchmidtLanterman incisures, which are cytoplasmic channels interrupting the compact myelin and characterized by distinct autotypic contacts, was increased in the three mutant lines. P0 -SCH-⌬39 -121 and conditionally deleted mice displayed exuberant wrapping of nonmyelinated fibers and short internodes, an abnormality possibly related to altered control of Schwann cell proliferation. In support of this hypothesis, Schwann cell number was increased along fibers before myelination in P0 -SCH-⌬39 -121 mice but not in those with C-terminal deletion. Schwann cell numbers were also more numerous in mice with conditional deletion. Thus, schwannomin plays an important role in the control of Schwann cell number and is necessary for the correct organization and regulation of axoglial heterotypic and glio-glial autotypic contacts.

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“…ErbB signaling, besides being required for DRG progenitor condensation, has a separate function required for the development of glial cells in the DRG and other tissues (Riethmacher et al, 1997;Britsch et al, 1998;Lyons et al, 2005;Chen et al, 2003;Sharghi-Namini et al, 2006;Pogoda et al, 2006) (reviewed by Britsch, 2007. We sought to examine the development of peripheral glia in ouchless mutants to determine whether this ErbB-dependent process is also dependent on Sorbs3.…”

Section: Peripheral Gliogenesis Is Normal In Ouchlessmentioning

confidence: 99%

Modulation of dorsal root ganglion development by ErbB signaling and the scaffold protein Sorbs3

et al. 2013

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The multipotent cells of the vertebrate neural crest (NC) arise at the dorsal aspect of the neural tube, then migrate throughout the developing embryo and differentiate into diverse cell types, including the sensory neurons and glia of the dorsal root ganglia (DRG). As multiple cell types are derived from this lineage, it is ideal for examining mechanisms of fate restriction during development. We have isolated a mutant, ouchless, that specifically fails to develop DRG neurons, although other NC derivatives develop normally. This mutation affects the expression of Sorbs3, a scaffold protein known to interact with proteins involved in focal adhesions and several signaling pathways. ouchless mutants share some phenotypic similarities with mutants in ErbB receptors, EGFR homologs that are implicated in diverse developmental processes and associated with several cancers; and ouchless interacts genetically with an allele of erbb3 in DRG neurogenesis. However, the defect in ouchless DRG neurogenesis is distinct from ErbB loss of function in that it is not associated with a loss of glia. Both ouchless and neurogenin1 heterozygous fish are sensitized to the effects of ErbB chemical inhibitors, which block the development of DRG in a dose-dependent manner. Inhibitors of MEK show similar effects on DRG neurogenesis. We propose a model in which Sorbs3 helps to integrate ErbB signals to promote DRG neurogenesis through the activation of MAPK and upregulation of neurogenin1.

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The Structural and Functional Integrity of Peripheral Nerves Depends on the Glial-Derived Signal Desert Hedgehog

Cited by 81 publications

References 65 publications

Desert Hedgehog Links Transcription Factor Sox10 to Perineurial Development

Desert Hedgehog Links Transcription Factor Sox10 to Perineurial Development

Tumor Suppressor Schwannomin/Merlin Is Critical for the Organization of Schwann Cell Contacts in Peripheral Nerves

Modulation of dorsal root ganglion development by ErbB signaling and the scaffold protein Sorbs3

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