When PNS Assembly Goes Awry: Familial Dysautonomia

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Over a century of elegant work has contributed to our understanding of how neural crest cells migrate throughout the embryo to give rise to the majority of cell types in the peripheral nervous system (PNS). This rich foundation is the basis for our lab's investigation of the cellular and molecular mechanisms that go awry to result in the developmental disorder of the PNS, Familial dysautonomia (FD). Three of the key clinical hallmarks of FD include a reduction in pain and temperature sensation, misregulation of the sympathetic nervous system, and impaired gastrointestinal tract function. The neurons in all of these systems derive from the neural crest. Consequently, a prevailing hypothesis in the field was that FD resulted from faulty neural crest migration. To test this hypothesis, we generated mice in which the gene that is mutated to cause FD, IKBKAP/ELP1, was deleted selectively from the neural crest. Interestingly, by the end of embryogenesis, we found that in fact the number of pain and temperature receptors in the dorsal root ganglia were significantly reduced as were sympathetic neurons in the superior cervical ganglia, recapitulating the human disease phenotype (George et al., 2013, PNAS). However, these studies also demonstrated that this selective reduction in neuronal number was not due to faulty neural crest cell migration. Rather, the reductions were due to (1) the death and premature differentiation of the Pax3+ pain and temperature progenitor cells and (2) exacerbated apoptosis of TrkA+ pain and temperature receptors. Interestingly, the TrkC+ proprioceptors developed normally, although they later die progressively in adulthood (Elisabetta Morini and Susan Slaughenhaupt, personal communication). Upon the completion of neurogenesis in the dorsal root and sympathetic ganglia, PNS axons must innervate their targets to fully differentiate. Our work and others (Jackson et al., 2014, Development; Abashidze et al., 2015, PLoS One) demonstrate that IkbkapElp1 is required for normal axon outgrowth and target innervation. These and other findings for how and why PNS development is disrupted in FD will be discussed.Support or Funding InformationNIH R01 NS086796; Dysautonomia FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.