title: IRS2 signalling is required for the development of a subset of sensory spinal neurons.
abstract: Insulin and insulin-like growth factor-I play important roles in the development and maintenance of neurons and glial cells of the nervous system. Both factors activate tyrosine kinase receptors, which signal through adapter proteins of the insulin receptor substrate (IRS) family. Although insulin and insulin-like growth factor-I receptors are expressed in dorsal root ganglia (DRG), the function of IRS-mediated signalling in these structures has not been studied. Here we address the role of IRS2-mediated signalling in murine DRG. Studies in cultured DRG neurons from different embryonic stages indicated that a subset of nerve growth factor-responsive neurons is also dependent on insulin for survival at very early time points. Consistent with this, increased apoptosis during gangliogenesis resulted in a partial loss of trkA-positive neurons in DRG of Irs2 mutant embryos. Analyses in adult Irs2(-/-)  mice revealed that unmyelinated fibre afferents, which express calcitonin gene-related peptide/substance P and isolectin B4, as well as some myelinated afferents to the skin were affected by the mutation. The diminished innervation of glabrous skin in adult Irs2(-/-)  mice correlated with longer paw withdrawal latencies in the hot-plate assay. Collectively, these findings indicate that IRS2 signalling is required for the proper development of spinal sensory neurons involved in the perception of pain.
authors.affiliation: Departamento de Biología Celular and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Universidad de Valencia, Doctor Moliner 50, 46100 Burjassot, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Chirivella
authors.forename: Marifé
authors.initials: M
authors.lastname: Cano-Jaimez
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Sánchez
authors.forename: Luis
authors.initials: L
authors.lastname: Herraez
authors.forename: José
authors.initials: J
authors.lastname: Carretero
authors.forename: Isabel
authors.initials: I
authors.lastname: Fariñas
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Burks
authors.forename: Martina
authors.initials: M
authors.lastname: Kirstein
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009619:Nociceptors / Q000166:cytology / Q000502:physiology*; D010147:Pain Measurement; D011247:Pregnancy; D020917:Receptor, trkA / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000166:cytology / Q000294:innervation / Q000378:metabolism
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D037102:Lectins; D020917:Receptor, trkA; D015740:Calcitonin Gene-Related Peptide