Joseph, N.M. et al. Neural crest stem cells undergo multilineage differentiation in developing peripheral nerves to generate endoneurial fibroblasts in addition to Schwann cells. Development 131, 5599-5612

Department of Cell Biology, Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands
Development (Impact Factor: 6.46). 12/2004; 131(22):5599-612. DOI: 10.1242/dev.01429
Source: PubMed


Neural crest stem cells (NCSCs) persist in peripheral nerves throughout late gestation but their function is unknown. Current models of nerve development only consider the generation of Schwann cells from neural crest, but the presence of NCSCs raises the possibility of multilineage differentiation. We performed Cre-recombinase fate mapping to determine which nerve cells are neural crest derived. Endoneurial fibroblasts, in addition to myelinating and non-myelinating Schwann cells, were neural crest derived, whereas perineurial cells, pericytes and endothelial cells were not. This identified endoneurial fibroblasts as a novel neural crest derivative, and demonstrated that trunk neural crest does give rise to fibroblasts in vivo, consistent with previous studies of trunk NCSCs in culture. The multilineage differentiation of NCSCs into glial and non-glial derivatives in the developing nerve appears to be regulated by neuregulin, notch ligands, and bone morphogenic proteins, as these factors are expressed in the developing nerve, and cause nerve NCSCs to generate Schwann cells and fibroblasts, but not neurons, in culture. Nerve development is thus more complex than was previously thought, involving NCSC self-renewal, lineage commitment and multilineage differentiation.

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Article: Joseph, N.M. et al. Neural crest stem cells undergo multilineage differentiation in developing peripheral nerves to generate endoneurial fibroblasts in addition to Schwann cells. Development 131, 5599-5612

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    • "). However, the investigators never found lacZ þ perineurial cells, and, thus, concluded that the perineurium did not share the same origin as these other two nerve elements (Joseph et al. 2004). "
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    ABSTRACT: Although the ultrastructure of peripheral nerves has been known for nearly 200 years, the developmental origins and functional roles of all five main components of these specialized nervous system conduits are still poorly understood. One of these understudied nerve elements, the perineurium, is a component of the blood-nerve barrier and is essential for protecting axons and their associated Schwann cells from ionic flux, toxins, and infection. However, until recently, it was thought that this vital nerve tissue was derived from the mesoderm and simply served a structural/barrier function with no other influence on the development, maintenance, or regeneration of peripheral nerves. Recent work in zebrafish using in vivo time-lapse imaging, genetic manipulation, and laser axotomy is shedding light on the origin and roles of this previously ignored glial nerve component and is changing how we view development of the nervous system. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 03/2015; 7(6). DOI:10.1101/cshperspect.a020511 · 8.68 Impact Factor
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    • "The perineurium is a critical peripheral nerve component responsible for ensheathing and protecting axons from environmental insult. Although the importance of the mature perineurium is not debated, its origin has been for many years, and the paucity of perineurial cell specific markers has made tracing its origin very difficult (Bunge et al., 1989; Joseph et al., 2004; Kucenas et al., 2008). Here, our results describe the characterization of Nkx2.2 expression in the PNS of mice using three distinct lines in combination with immunohistochemistry and in situ hybridization. "
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    ABSTRACT: Background: All vertebrate peripheral nerves connect the central nervous system (CNS) with targets in the periphery and are composed of axons, layers of ensheathing glia and connective tissue. Although the structure of these conduits is well established, very little is known about the origin and developmental roles of some of their elements. One understudied component, the perineurium, ensheaths nerve fascicles and is a component of the blood-nerve-barrier. In zebrafish, the motor nerve perineurium is composed of CNS-derived nkx2.2a(+) perineurial glia, which establish the motor exit point (MEP) during development. To determine if mouse perineurial cells also originate within the CNS and perform a similar function, we created a Nkx2.2:EGFP transgenic reporter line. Results: In conjunction with RNA expression analysis and antibody labeling, we observed Nkx2.2(+) cells along peripheral motor nerves at all stages of development and in adult tissue. Additionally, in mice lacking Nkx2.2, we demonstrate that Nkx2.2(+) perineurial glia are essential for motor nerve development and Schwann cell differentiation. Conclusions: Our studies reveal that a subset of mouse perineurial cells are CNS-derived, express Nkx2.2, and are essential for motor nerve development. This work highlights an under-appreciated but essential contribution of CNS-derived cells to the development of the mammalian peripheral nervous system (PNS).
    Developmental Dynamics 09/2014; 243(9). DOI:10.1002/dvdy.24158 · 2.38 Impact Factor
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    • "SAPs play an important role in development of the sympathetic PNS and are putative cells of origin of neuroblastoma. Efforts have been made to isolate these cells from PNS tissues of rodents such as sciatic nerve, gut or sympathetic ganglia [32]–[36], and from bone marrow, carotid body, cornea, dental tissue, dorsal root ganglion, heart, palatum and skin of adult rodents [6]. As isolation of NCSCs and SAPs is hampered by the small number and limited life span of the cells that can be procured, murine neural tube explant cells have been immortalized by oncogenes [37], [38]. "
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    ABSTRACT: Sympathoadrenergic progenitor cells (SAPs) of the peripheral nervous system (PNS) are important for normal development of the sympathetic PNS and for the genesis of neuroblastoma, the most common and often lethal extracranial solid tumor in childhood. However, it remains difficult to isolate sufficient numbers of SAPs for investigations. We therefore set out to improve generation of SAPs by using two complementary approaches, differentiation from murine embryonic stem cells (ESCs) and isolation from postnatal murine adrenal glands. We provide evidence that selecting for GD2 expression enriches for ESC-derived SAP-like cells and that proliferating SAP-like cells can be isolated from postnatal adrenal glands of mice. These advances may facilitate investigations about the development and malignant transformation of the sympathetic PNS.
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