The familial dysautonomia disease geneIKBKAPis required in the developing and adult mouse central nervous system.
Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the geneIKBKAPthat encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator. Since mutations in other Elongator subunits (ELP2 to ELP4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential requirement forIkbkapin the CNS of mice.The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While signs and pathology of FD have been noted in the CNS, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement forIkbkapin the CNS. Here, we report, using a novel mouse line in whichIkbkapis deleted solely in the nervous system, that not only isIkbkapwidely 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 requireIkbkapfor 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 includes impairments in learning and memory. Collectively, these data reveal an essential function forIkbkapthat extends beyond the peripheral nervous system to CNS development and function. With the identification of discrete CNS cell types and structures that depend onIkbkap, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed.
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.
Marta
M
Chaverra
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.|Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT 59101, USA.
Lynn
L
George
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.
Marc
0000-0001-5359-2570
M
Mergy
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.
Hannah
0000-0001-7703-8865
H
Waller
Department of Psychology, Montana State University, Bozeman, MT 59717, USA.
Katharine
0000-0002-9334-4894
K
Kujawa
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.
Connor
0000-0003-0014-0735
C
Murnion
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.
Ezekiel
0000-0001-9666-372X
E
Sharples
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.|University of Washington, School of Medicine, Seattle, WA 98195, USA.
Julian
J
Thorne
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.
Nathaniel
0000-0002-9494-4111
N
Podgajny
McLaughlin Research Institute, Great Falls, MT 59405, USA.
Andrea
A
Grindeland
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.
Yumi
Y
Ueki
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.
Steven
S
Eiger
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.
Cassie
C
Cusick
Department of Psychology, Montana State University, Bozeman, MT 59717, USA.
A Michael
AM
Babcock
McLaughlin Research Institute, Great Falls, MT 59405, USA.
George A
GA
Carlson
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA lefcort@montana.edu.
Frances
0000-0002-2064-8678
F
Lefcort
D000818:Animals; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002490:Central Nervous System / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D004402:Dysautonomia, Familial / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000473:pathology
D002352:Carrier Proteins; C491968:Ikbkap protein, mouse; D047908:Intracellular Signaling Peptides and Proteins
Elongator; Familial dysautonomia; Hereditary sensory and autonomic neuropathy