title: Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3+ progenitors and peripheral neurons.
abstract: Familial dysautonomia (FD) is a devastating developmental and progressive peripheral neuropathy caused by a mutation in the gene inhibitor of kappa B kinase complex-associated protein (IKBKAP). To identify the cellular and molecular mechanisms that cause FD, we generated mice in which Ikbkap expression is ablated in the peripheral nervous system and identify the steps in peripheral nervous system development that are Ikbkap-dependent. We show that Ikbkap is not required for trunk neural crest migration or pathfinding, nor for the formation of dorsal root or sympathetic ganglia, or the adrenal medulla. Instead, Ikbkap is essential for the second wave of neurogenesis during which the majority of tropomyosin-related kinase A (TrkA(+)) nociceptors and thermoreceptors arise. In its absence, approximately half the normal complement of TrkA(+) neurons are lost, which we show is partly due to p53-mediated premature differentiation and death of mitotically-active progenitors that express the paired-box gene Pax3 and give rise to the majority of TrkA(+) neurons. By the end of sensory development, the number of TrkC neurons is significantly increased, which may result from an increase in Runx3(+) cells. Furthermore, our data demonstrate that TrkA(+) (but not TrkC(+)) sensory and sympathetic neurons undergo exacerbated Caspase 3-mediated programmed cell death in the absence of Ikbkap and that this death is not due to a reduction in nerve growth factor synthesis. In summary, these data suggest that FD does not result from a failure in trunk neural crest migration, but rather from a critical function for Ikbkap in TrkA progenitors and TrkA(+) neurons.
authors.affiliation: Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717.
authors.forename: Lynn
authors.initials: L
authors.lastname: George
authors.forename: Marta
authors.initials: M
authors.lastname: Chaverra
authors.forename: Lindsey
authors.initials: L
authors.lastname: Wolfe
authors.forename: Julian
authors.initials: J
authors.lastname: Thorne
authors.forename: Mattheson
authors.initials: M
authors.lastname: Close-Davis
authors.forename: Amy
authors.initials: A
authors.lastname: Eibs
authors.forename: Vickie
authors.initials: V
authors.lastname: Riojas
authors.forename: Andrea
authors.initials: A
authors.lastname: Grindeland
authors.forename: Miranda
authors.initials: M
authors.lastname: Orr
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.forename: Frances
authors.initials: F
authors.lastname: Lefcort
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004402:Dysautonomia, Familial / Q000503:physiopathology*; D005147:Facial Bones / Q000473:pathology; D017353:Gene Deletion; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D009432:Neural Crest / Q000378:metabolism*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D017933:Peripheral Nervous System / Q000503:physiopathology
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; C491968:Ikbkap protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; C068686:Pax3 protein, mouse