Publications by Colleges and Departments (MSU - Bozeman)
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Item Elongator and codon bias regulate protein levels in mammalian peripheral neurons(2018-03) Goffena, Joy; Lefcort, Frances; Zhang, Yongqing; Lehrmann, Elin; Chaverra, Marta; Felig, Jehremy; Walters, Joseph; Buksch, Richard; Becker, Kevin G.; George, LynnFamilial dysautonomia (FD) results from mutation in IKBKAP/ELP1, a gene encoding the scaffolding protein for the Elongator complex. This highly conserved complex is required for the translation of codon-biased genes in lower organisms. Here we investigate whether Elongator serves a similar function in mammalian peripheral neurons, the population devastated in FD. Using codon-biased eGFP sensors, and multiplexing of codon usage with transcriptome and proteome analyses of over 6,000 genes, we identify two categories of genes, as well as specific gene identities that depend on Elongator for normal expression. Moreover, we show that multiple genes in the DNA damage repair pathway are codon-biased, and that with Elongator loss, their misregulation is correlated with elevated levels of DNA damage. These findings link Elongator's function in the translation of codon-biased genes with both the developmental and neurodegenerative phenotypes of FD, and also clarify the increased risk of cancer associated with the disease.Item The Familial Dysautonomia disease gene, Ikbkap/Elp1, is required in the developing and adult central nervous system(2017-02) Chaverra, Marta; George, Lynn; Mergy, Marc; Waller, Hannah R.; Kujawa, Katharine J.; Murnion, Connor; Sharples, Ezekiel; Thorne, Julian; Podgajny, Nathaniel; Grindeland, Andrea; Ueki, Yumi; Eiger, Steven; Cusick, Cassie; Babcock, A. Michael; Carlson, George A.; Lefcort, FrancesHereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN Type III, Familial Dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit for a multi-subunit complex Elongator. Since mutations in other Elongator subunits (ELP2-4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential CNS requirement for Ikbkap/Elp1 The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While CNS signs and pathology have been noted in FD, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap/Elp1 in the CNS. Here we report using a novel mouse line in which Ikbkap/Elp1 is deleted solely in the nervous system, that not only is Ikbkap/Elp1 widely expressed in the embryonic and adult CNS, but its deletion perturbs both the development of cortical neurons and their survival in adulthood. Primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells are reduced in number and disorganized. Furthermore, we report that in the adult CNS, both autonomic and non-autonomic neuronal populations require Ikbkap for survival, including spinal motor and cortical neurons. In addition, the mice developed kyphoscoliosis, an FD hallmark, indicating its neuropathic etiology. Ultimately, these perturbations manifest in a developmental and progressive neurodegenerative condition that include impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap/Elp1 that extends beyond the PNS, to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap/Elp1, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed.Item TrkB/BDNF signalling patterns the sympathetic nervous system(2015-09) Kasemeier-Kulesa, Jennifer S.; Morrison, Jason A.; Lefcort, Frances; Kulesa, Paul M.The sympathetic nervous system is essential for maintaining mammalian homeostasis. How this intricately connected network, composed of preganglionic neurons that reside in the spinal cord and post-ganglionic neurons that comprise a chain of vertebral sympathetic ganglia, arises developmentally is incompletely understood. This problem is especially complex given the vertebral chain of sympathetic ganglia derive secondarily from the dorsal migration of ‘primary’ sympathetic ganglia that are initially located several hundred microns ventrally from their future pre-synaptic partners. Here we report that the dorsal migration of discrete ganglia is not a simple migration of individual cells but a much more carefully choreographed process that is mediated by extensive interactions of pre-and post-ganglionic neurons. Dorsal migration does not occur in the absence of contact with preganglionic axons, and this is mediated by BDNF/TrkB signalling. Thus BDNF released by preganglionic axons acts chemotactically on TrkB-positive sympathetic neurons, to pattern the developing peripheral nervous system.