Spatiotemporal Gradient of Cortical Neuron Death Contributes to Microcephaly in Knock-In Mouse Model of Ligase 4 Syndrome

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dc.contributor.authorLun, Melody P.
dc.contributor.authorShannon, Morgan L.
dc.contributor.authorKeles, Sevgi
dc.contributor.authorReisli, Ismail
dc.contributor.authorLuche, Nicole
dc.contributor.authorRyan, Douglas
dc.contributor.authorCapuder, Kelly
dc.date.accessioned2024-02-23T14:02:03Z
dc.date.available2024-02-23T14:02:03Z
dc.date.issued2019
dc.departmentNEÜen_US
dc.description.abstractCells of the developing central nervous system are particularly susceptible to formation of double-stranded DNA breaks (DSBs) arising from physiological and/or environmental insults. Therefore, efficient repair of DSBs is especially vital for maintaining cellular health and proper functioning in the developing brain. Here, increased expression of DSB initiating and nonhomologous end joining repair machinery in newborn neurons in the developing brains of both mouse and human are demonstrated. In parallel, the first characterization is provided of the brain phenotype in the Lig4(R278H/R278H) (Lig4(R/R)) mouse model of DNA Ligase 4 (LIG4) syndrome, in which a hypomorphic Lig4 mutation, originally identified in patients, impedes nonhomologous end joining. It is shown that Lig4(R/R) mice develop nonprogressive microcephaly, resulting primarily from apoptotic death of newborn neurons that is both spatially and temporally specific during peak cortical neurogenesis. This apoptosis leads to a reduction in neurons throughout the postnatal cerebral cortex, but with a more prominent impact on those of the lower cortical layers. Together, these findings begin to uncover the pathogenesis of microcephaly in LIG4 syndrome and open avenues to more focused investigations on the critical roles of DSB formation and repair in vulnerable neuronal populations of the brain.en_US
dc.description.sponsorshipNew York Stem Cell Foundation; BCH IDDRC [1U54HD090255]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIHen_US
dc.description.sponsorshipSupported by the New York Stem Cell Foundation (M.K.L.); BCH IDDRC 1U54HD090255; and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH (L.D.N.). M.K.L. is a New York Stem Cell Foundation Robertson Investigator.en_US
dc.identifier.doi10.1016/j.ajpath.2019.08.010
dc.identifier.endpage2449en_US
dc.identifier.issn0002-9440
dc.identifier.issn1525-2191
dc.identifier.issue12en_US
dc.identifier.pmid31541646en_US
dc.identifier.scopus2-s2.0-85075197196en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage2440en_US
dc.identifier.urihttps://doi.org/10.1016/j.ajpath.2019.08.010
dc.identifier.urihttps://hdl.handle.net/20.500.12452/11557
dc.identifier.volume189en_US
dc.identifier.wosWOS:000501397900008en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherElsevier Science Incen_US
dc.relation.ispartofAmerican Journal Of Pathologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleSpatiotemporal Gradient of Cortical Neuron Death Contributes to Microcephaly in Knock-In Mouse Model of Ligase 4 Syndromeen_US
dc.typeArticleen_US

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