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    • These fate analyses relied on the

    2018-10-24

    These fate analyses relied on the restriction of Krox20 expression to BC hydroxylase inhibitor during early PNS development. However, from embryonic day 15.5 (E15.5), Krox20 also is expressed in Schwann cells (Topilko et al., 1994), thereby preventing later analysis of BC derivatives. To circumvent this problem, we have generated a Cre recombinase knockin in a novel BC-specific marker, Prss56, previously known as L20 (Coulpier et al., 2009), and we used it to trace BC cell derivatives in the embryo and the adult. Prss56 encodes a trypsin-like serine protease and its mutation in the retina has been associated with microphtalmia in humans and mice (Nair et al., 2011). In this study, we show that, during embryogenesis, some of the BC derivatives rapidly migrate along the peripheral nerves and settle in the skin, where they provide terminal glia as well as multipotent progenitors that have broad differentiation capacities in culture and after transplantation into adult mice. This work, therefore, reveals the embryonic origin, pathway of migration, and in vivo neurogenic potential of a multipotent stem cell-like population in the skin.
    Results
    Discussion This study builds on previous observations that the NC contribution to PNS formation occurs in two waves (Maro et al., 2004), with one population migrating directly to their target locations, while the other makes a stop at the level of the BCs. In contrast to what was previously thought (Maro et al., 2004), we establish that the two waves make similar qualitative contributions in terms of neuronal subtypes in the DRG. Along peripheral nerves of the trunk, the BCs provide the entire proximal Schwann cell nerve root component, as well as a large part of the glia covering the distal parts of skin nerves, whereas the direct NC contribution appears largely restricted to the intermediate part of the nerves. These distinct origins may underlie functional differences between glial populations at different levels along the nerves. These data have to be considered in the context of recent studies that have shown that embryonic peripheral nerves contain progenitor cells with NC-like potential. Specifically, the early glial components of peripheral nerves, the Schwann cell precursors, possess extensive differentiation capacities as, in addition to Schwann cells (Jessen et al., 2015), they can give rise to melanocytes in the skin (Adameyko et al., 2009), parasympathetic neurons (Dyachuk et al., 2014; Espinosa-Medina et al., 2014), and mesenchymal derivatives in the tooth (Kaukua et al., 2014). However, BC cells appear distinct from these pluripotent glial populations by their location at the PNS/CNS boundary, the expression of specific markers such as Krox20 and Prss56 (Coulpier et al., 2009), and the identity of their derivatives. Furthermore, some BC derivatives maintain their pluripotency in adult tissues, while the pluripotency of Schwann cell precursors is restricted to a specific developmental period. In the skin, we have shown that BC derivatives give rise to at least three glial populations as follows: Schwann cells (mainly non-myelinating) associated with subcutaneous and dermal nerves, and two types of terminal Schwann cells, associated with lanceolate endings or free nerve endings. Lanceolate endings are specialized sensory organs that detect hair movement (Abraira and Ginty, 2013). They form a palisade structure surrounding the hair follicle and are composed of terminal fibers carrying rapidly adapting low-threshold mechanoreceptors (Aβ, Aδ, and C) (Abraira and Ginty, 2013). The terminal Schwann cells are involved in the maintenance of the lanceolate complex (Li and Ginty, 2014) and could play a role in calcium signaling (Takahashi-Iwanaga et al., 2008). Free nerve endings are non-specialized cutaneous sensory receptors that are involved in the perception of touch, pressure, and pain (Abraira and Ginty, 2013). In contrast to their name, free nerve endings also are associated with terminal Schwann cells. Terminal Schwann cells have been studied only by electron microscopy and present a very peculiar morphology, with numerous cytoplasmic protrusions covering the axons at the dermis/epidermis boundary (Cauna, 1973). We provide here a genetic marker that enables optical observations of these cells. Their morphology resembles that of perisynaptic Schwann cells (PSCs), which cap motor nerve terminals at the neuromuscular junction (Balice-Gordon, 1996). PSCs are involved in sensing and modulating synaptic transmission through the specific expression of neurotransmitter receptors and ion channels on their surface (Auld and Robitaille, 2003). Given their similarity with PSCs in terms of terminal location and morphology, we speculate that Schwann cells associated with free nerve endings might play a direct role in depolarizing axon membranes. The Prss56 line allows easy identification of these atypical Schwann cells and should facilitate their detailed characterization.