| Experiment Id | GSE80107 | Name | Transcriptome analyses of the nervous system of Familial Dysautonomia-model mice identify novel cellular pathways dependent on Ikbkap/Elp1 (CNS) |
| Experiment Type | transcription profiling by array | Study Type | WT vs. Mutant |
| Source | GEO | Curation Date | 2022-11-02 |
| description | Familial Dysautonomia (FD; OMIM #223900) is both a developmental and progressive autosomal recessive neurodegenerative disorder that results from a nervous-system reduction in the IKAP/ELP1 protein due to a mutation in a splice acceptor site of the IKBKAP/ELP1 gene. The function of this gene in the nervous system is unresolved. To obviate the embryonic lethality of mice completely null for Ikbkap, we generated conditional knock out (CKO) mouse models for FD that recapitulate hallmarks of the human disease. To derive insight into potential intracellular functions for Ikbkap, we conducted a genome-wide transcriptome analysis of both the peripheral and central nervous systems from Ikbkap CKO mice, and identify over 100 shared misregulated genes that reveal roles for IKAP in several metabolic and signaling pathways in addition to synaptic transmission. Importantly, our data are the first to demonstrate that in the absence of IKAP, neurons undergo intracellular stress that is marked by transcriptional elevations in ATF5, p53, and several CREB target genes, as well as an increase in reactive oxygen species. These data will aid in the identification of common upstream and downstream targets for therapeutics for preventing the progressive demise of neurons in FD and potentially other neuropathies. Examining the major genetic pathways that require IKAP are hampered by that Ikbkap null mice are embryonic lethal (E10), but can circumvented by genome-wide transcriptome analysis in the brains in adult Tuba1a-Cre;IkbkapLoxP/LoxP mice, which live on average 6 months. These lines were obtained by crossing mice homozygous for a floxed allele of Ikbkap (exon 4) mice to mice that are heterozygous for this floxed allele, and a Tuba1a-Cre transgene. For this study, brain tissue (cerebellum and brainstem) was removed from 2-5 month old adult Tuba1a-cre;IkbkapLoxP/LoxP mice and stored at -80 until RNA was isolated. Four wildtype and four conditional knock-out animals were analyzed for this experiment. |
