Gli1 Regulates the Postnatal Acquisition of Peripheral Nerve Architecture

Abstract

Peripheral nerves are organized into discrete compartments. Axons, Schwann cells (SCs), and endoneurial fibroblasts (EFs) reside within the endoneurium and are surrounded by the perineurium, a cellular sheath comprised of layers of perineurial glia (PNG). SC secretion of Desert Hedgehog (Dhh) regulates this organization. In Dhh nulls, the perineurium is deficient and the endoneurium is subdivided into small compartments termed minifascicles. Human Dhh mutations cause a neuropathy with similar defects.Here we examine the role of Gli1, a canonical transcriptional effector of hedgehog signaling, in regulating peripheral nerve organization in mice of both genders. We identify PNG, EFs, and pericytes as Gli1-expressing cells by genetic fate mapping. Although expression of Dhh by SCs and Gli1 in target cells is coordinately regulated with myelination, Gli1 expression unexpectedly persists in Dhh null EFs. Thus, Gli1 is expressed in EFs noncanonically (i.e., independent of hedgehog signaling). Gli1 and Dhh also have nonredundant activities. Unlike Dhh nulls, Gli1 nulls have a normal perineurium. Like Dhh nulls, Gli1 nulls form minifascicles, which we show likely arise from EFs. Thus, Dhh and Gli1 are independent signals: Gli1 is dispensable for perineurial development but functions cooperatively with Dhh to drive normal endoneurial development. During development, Gli1 also regulates endoneurial extracellular matrix production, nerve vascular organization, and has modest, nonautonomous effects on SC sorting and myelination of axons. Finally, in adult nerves, induced deletion of Gli1 is sufficient to drive minifascicle formation. Thus, Gli1 regulates the development and is required to maintain the endoneurial architecture of peripheral nerves.

Fibroblast diversification is an embryonic process dependent on muscle contraction

“…S6 I-J). Notably, Schwan cells’ derived Desert hedgehog ( Dhh ) has been reported to regulate the structural and functional integrity of peripheral nerves (Parmantier et al, 1999; Sharghi-Namini et al, 2006; Zotter et al, 2022). Accordingly, Cldn1+ fibroblasts express the hedgehog pathway target genes Ptch1 and Gli1 (Fig.…”

Molecular characterization of the intact mouse muscle spindle using a multi-omics approach

“…It was previously suggested that the outer spindle capsule is part of the perineural sheath in the peripheral nervous system ( Shantha et al, 1968 ). Recently, Gli1 was shown to be expressed by perineural glial cells ( Zotter et al, 2022 ). Examination of our data showed that Gli1 transcripts were significantly upregulated in the muscle spindle samples as compared to the extrafusal fiber samples (log fold change 3.57; Supplementary file 1 ).…”

The role of Hedgehog and Notch signaling pathway in cancer

“…Notch and Hedgehog (Hh) were first described in Drosophila by Thomas Hunt Morgan in 1917 and by Nusslein-Volhard and Wieschaus in 1980 [1,2]. Both signaling pathways exist widely in vertebrates and invertebrates, are highly primordial and conserved in evolution, and are intimately involved in the fate determination of cells [3,4], differentiation of tissues [5], development of organs [2,[6][7][8][9], formation of embryos [10,11] and homeostasis in organisms [12]. Abnormalities in the modulation of both pathways during embryonic development may contribute to malformations [13][14][15] and disorders [16][17][18][19].…”