Loss of Elp1 in cerebellar granule cell progenitors models ataxia phenotype of Familial Dysautonomia.

Autor: Arnskötter F; Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., da Silva PBG; Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany., Schouw ME; Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany., Lukasch C; Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany., Bianchini L; Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., Sieber L; Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany., Garcia-Lopez J; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA; Center of Excellence in Neuro-Oncology Sciences (CENOS), St. Jude Children's Research Hospital, Memphis, TN, USA; Department of In vivo Pharmacology-Immunology, Tempest Therapeutics, Brisbane, CA, USA., Ahmad ST; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA; Center of Excellence in Neuro-Oncology Sciences (CENOS), St. Jude Children's Research Hospital, Memphis, TN, USA., Li Y; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA; Center of Excellence in Neuro-Oncology Sciences (CENOS), St. Jude Children's Research Hospital, Memphis, TN, USA., Lin H; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA; Center of Excellence in Neuro-Oncology Sciences (CENOS), St. Jude Children's Research Hospital, Memphis, TN, USA., Joshi P; Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany., Spänig L; Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., Radoš M; Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany., Roiuk M; Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany., Sepp M; Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany., Zuckermann M; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany; Division of Pediatric Neuro-Oncology, Preclinical Modeling Group, German Cancer Research Center (DKFZ), Heidelberg, Germany., Northcott PA; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA; Center of Excellence in Neuro-Oncology Sciences (CENOS), St. Jude Children's Research Hospital, Memphis, TN, USA., Patrizi A; Schaller Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany., Kutscher LM; Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany. Electronic address: l.kutscher@kitz-heidelberg.de.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2024 Sep; Vol. 199, pp. 106600. Date of Electronic Publication: 2024 Jul 10.
DOI: 10.1016/j.nbd.2024.106600
Abstrakt: Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have also been described. Although ELP1 expression remains high in the normal developing and adult cerebellum, its role in cerebellar development is unknown. To explore the role of Elp1 in the cerebellum, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1 cKO ) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent as early as 7 days after birth, when Elp1 cKO animals also had fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 in the developing cerebellum, and suggests that loss of Elp1 in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.
Competing Interests: Declaration of competing interest The authors declare that they have no competing interests.
(Copyright © 2023. Published by Elsevier Inc.)
Databáze: MEDLINE
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