TM2D genes regulate Notch signaling and neuronal function in Drosophila.

Autor: Salazar JL; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, Texas, United States of America.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America., Yang SA; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, Texas, United States of America.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America., Lin YQ; The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, Sydney, Australia., Li-Kroeger D; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.; Department of Neurology, BCM, Houston, Texas, United States of America.; Center for Alzheimer's and Neurodegenerative Diseases, BCM, Houston, Texas, United States of America., Marcogliese PC; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, Texas, United States of America.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America., Deal SL; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.; Program in Developmental Biology, BCM, Houston, Texas, United States of America., Neely GG; The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, Sydney, Australia., Yamamoto S; Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, Texas, United States of America.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.; Center for Alzheimer's and Neurodegenerative Diseases, BCM, Houston, Texas, United States of America.; Program in Developmental Biology, BCM, Houston, Texas, United States of America.; Development, Disease Models & Therapeutics Graduate Program, BCM, Houston, Texas, United States of America.; Department of Neuroscience, BCM, Houston, Texas, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2021 Dec 14; Vol. 17 (12), pp. e1009962. Date of Electronic Publication: 2021 Dec 14 (Print Publication: 2021).
DOI: 10.1371/journal.pgen.1009962
Abstrakt: TM2 domain containing (TM2D) proteins are conserved in metazoans and encoded by three separate genes in each model organism species that has been sequenced. Rare variants in TM2D3 are associated with Alzheimer's disease (AD) and its fly ortholog almondex is required for embryonic Notch signaling. However, the functions of this gene family remain elusive. We knocked-out all three TM2D genes (almondex, CG11103/amaretto, CG10795/biscotti) in Drosophila and found that they share the same maternal-effect neurogenic defect. Triple null animals are not phenotypically worse than single nulls, suggesting these genes function together. Overexpression of the most conserved region of the TM2D proteins acts as a potent inhibitor of Notch signaling at the γ-secretase cleavage step. Lastly, Almondex is detected in the brain and its loss causes shortened lifespan accompanied by progressive motor and electrophysiological defects. The functional links between all three TM2D genes are likely to be evolutionarily conserved, suggesting that this entire gene family may be involved in AD.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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