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[P41]: Skin‐derived precursors: A neural crest‐like precursor capable of remyelinating the injured spinal cord
Author(s) -
Biernaskie J.,
Sparling J.,
McKenzie I.,
Xie R.,
Liu J.,
Lam C.,
Wong A.,
Sutherland D.,
Choo A.,
Shan C.,
Miller F.,
Tetzlaff W.
Publication year - 2006
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2006.09.104
Subject(s) - columbia university , university hospital , sick child , clinical neuropsychology , library science , media studies , history , medicine , sociology , family medicine , pediatrics , computer science , medical education
Developing sympathetic neurons require neurotrophins such as nerve growth factor (NGF) and neurotrophin 3 (NT-3) for axon guidance, target innervation, and ultimately survival through local and retrograde axonal signaling in vivo. While the importance of neurotrophins in these developmental processes is well documented, the downstream mediators of neurotrophin signaling are largely unknown. Early Growth Response genes (Egr1, Egr2, Egr3, and Egr4) encode transcription factors that regulate target genes important for growth and differentiation. Egr1 regulation is coupled to NGF signaling and subsequent differentiation of pheochromocytomaand neuroblastoma-derived cell lines yet Egr1-deficient mice have no sympathetic nervous system defects. We show that a related Egr gene, Egr3, plays an important role in sympathetic neuron development. We cultured primary sympathetic neurons to determine the role of Egr3 in neurotrophin-mediated signaling pathways effecting survival and neurite outgrowth. Also, we quantified neuronal survival in vivo using stereological neuron counts and cleaved-caspase 3 immunohistochemistry. Finally, we utilized tyrosine hydroxylase immunohistochemistry and dopaminehydroxylaselacz reporter mice bred to Egr3−/− mice to examine target tissue innervation. We show that Egr3 expression is coupled to NGF and NT3 signaling in sympathetic neurons. Moreover, a deficiency of Egr3 in vivo compromises sympathetic neuron survival. In Egr3−/− mice, a subpopulation of sympathetic neurons undergoes apoptosis after the onset of neurotrophin dependence, resulting in a loss of one-third of neurons within superior cervical ganglia postnatally. However, Egr3-deficient neurons do not exhibit increased cell death when cultured with exogenous NGF. Finally, we show that Egr3 deficiency disrupts target tissue innervation. Egr3−/− mice exhibit a complete loss of sympathetic innervation of some target tissues and a partial decrease in innervation of others. From these data, we hypothesize that Egr3 is a downstream effector of neurotrophin signaling in vivo and thereby is critical for sympathetic neuron development and survival.