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      A Neurotrophic Mechanism Directs Sensory Nerve Transit in Cranial Bone

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          SUMMARY

          The flat bones of the skull are densely innervated during development, but little is known regarding their role during repair. We describe a neurotrophic mechanism that directs sensory nerve transit in the mouse calvaria. Patent cranial suture mesenchyme represents an NGF (nerve growth factor)-rich domain, in which sensory nerves transit. Experimental calvarial injury upregulates Ngf in an IL-1β/TNF-α-rich defect niche, with consequent axonal ingrowth. In calvarial osteoblasts, IL-1β and TNF-α stimulate Ngf and downstream NF-κB signaling. Locoregional deletion of Ngf delays defect site re-innervation and blunted repair. Genetic disruption of Ngf among LysM-expressing macrophages phenocopies these observations, whereas conditional knockout of Ngf among Pdgfra-expressing cells does not. Finally, inhibition of TrkA catalytic activity similarly delays re-innervation and repair. These results demonstrate an essential role of NGF-TrkA signaling in bone healing and implicate macrophage-derived NGF-induced ingrowth of skeletal sensory nerves as an important mediator of this repair.

          In Brief

          Meyers et al. describe the role of skeletal sensory nerves in cranial bone repair. The authors demonstrate several necessary aspects of membranous bone healing, including influx of nerve growth factor (NGF)-expressing macrophages after injury, followed by skeletal sensory nerve ingrowth to positively regulate bone repair.

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          Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels.

          During endochondral bone development, the first osteoblasts differentiate in the perichondrium surrounding avascular cartilaginous rudiments; the source of trabecular osteoblasts inside the later bone is, however, unknown. Here, we generated tamoxifen-inducible transgenic mice bred to Rosa26R-LacZ reporter mice to follow the fates of stage-selective subsets of osteoblast lineage cells. Pulse-chase studies showed that osterix-expressing osteoblast precursors, labeled in the perichondrium prior to vascular invasion of the cartilage, give rise to trabecular osteoblasts, osteocytes, and stromal cells inside the developing bone. Throughout the translocation, some precursors were found to intimately associate with invading blood vessels, in pericyte-like fashion. A similar coinvasion occurs during endochondral healing of bone fractures. In contrast, perichondrial mature osteoblasts did not exhibit perivascular localization and remained in the outer cortex of developing bones. These findings reveal the specific involvement of immature osteoblast precursors in the coupled vascular and osteogenic transformation essential to endochondral bone development and repair. 2010 Elsevier Inc. All rights reserved.
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            Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate.

            The limb blastemal cells of an adult salamander regenerate the structures distal to the level of amputation, and the surface protein Prod 1 is a critical determinant of their proximodistal identity. The anterior gradient protein family member nAG is a secreted ligand for Prod 1 and a growth factor for cultured newt blastemal cells. nAG is sequentially expressed after amputation in the regenerating nerve and the wound epidermis-the key tissues of the stem cell niche-and its expression in both locations is abrogated by denervation. The local expression of nAG after electroporation is sufficient to rescue a denervated blastema and regenerate the distal structures. Our analysis brings together the positional identity of the blastema and the classical nerve dependence of limb regeneration.
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              Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.

              Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation. The genetic basis for CIPA is unknown. Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. Mice lacking the gene for TrkA, a receptor tyrosine kinase for NGF, share dramatic phenotypic features of CIPA, including loss of responses to painful stimuli, although anhidrosis is not apparent in these animals. We therefore considered the human TRKA homologue as a candidate for the CIPA gene. The mRNA and genomic DNA encoding TRKA were analysed in three unrelated CIPA patients who had consanguineous parents. We detected a deletion-, splice- and missense-mutation in the tyrosine kinase domain in these three patients. Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans. These results also implicate genes encoding other TRK and neurotrophin family members as candidates for developmental defect(s) of the nervous system.
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                Author and article information

                Journal
                101573691
                39703
                Cell Rep
                Cell Rep
                Cell reports
                2211-1247
                3 June 2020
                26 May 2020
                05 July 2020
                : 31
                : 8
                : 107696
                Affiliations
                [1 ]Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
                [2 ]Department of Orthopaedics, Johns Hopkins University, Baltimore, MD 21205, USA
                [3 ]Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA
                [4 ]Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK
                [5 ]Department of Orthopaedics and Traumatology, University of Verona, 37129 Verona, Italy
                [6 ]These authors contributed equally
                [7 ]Lead Contact
                Author notes

                AUTHOR CONTRIBUTIONS

                Conception and Design, Funding, and Final Manuscript Approval, A.W.J. and T.L.C.; Acquisition, Analysis, and Interpretation of Data, C.A.M., S.L., T.S., S.N., J.X., Y.W., Z.L., S.M., L.C., and Y.G.; Donation of Materials, L.M.; Manuscript Preparation, C.A.M., S.L., T.S., S.M., A.W.J., and T.L.C.

                [* ]Correspondence: tclemen5@ 123456jhmi.edu (T.L.C.), awjames@ 123456jhmi.edu (A.W.J.)
                Article
                NIHMS1598120
                10.1016/j.celrep.2020.107696
                7335423
                32460020
                d3e43127-d123-41f6-be9b-05de23b80e47

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Cell biology
                Cell biology

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