title: APC/C-Cdh1 coordinates neurogenesis and cortical size during development.
abstract: The morphology of the adult brain is the result of a delicate balance between neural progenitor proliferation and the initiation of neurogenesis in the embryonic period. Here we assessed whether the anaphase-promoting complex/cyclosome (APC/C) cofactor, Cdh1--which regulates mitosis exit and G1-phase length in dividing cells--regulates neurogenesis in vivo. We use an embryo-restricted Cdh1 knockout mouse model and show that functional APC/C-Cdh1 ubiquitin ligase activity is required for both terminal differentiation of cortical neurons in vitro and neurogenesis in vivo. Further, genetic ablation of Cdh1 impairs the ability of APC/C to promote neurogenesis by delaying the exit of the progenitor cells from the cell cycle. This causes replicative stress and p53-mediated apoptotic death resulting in decreased number of cortical neurons and cortex size. These results demonstrate that APC/C-Cdh1 coordinates cortical neurogenesis and size, thus posing Cdh1 in the molecular pathogenesis of congenital neurodevelopmental disorders, such as microcephaly.
authors.affiliation: 1] Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Fundación IECSCYL, 37007 Salamanca, Spain [2] Instituto de Biología Funcional y Genómica (IBFG), CSIC/Universidad de Salamanca, IBSAL, 37007 Salamanca, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Delgado-Esteban
authors.forename: Irene
authors.initials: I
authors.lastname: García-Higuera
authors.forename: Carolina
authors.initials: C
authors.lastname: Maestre
authors.forename: Sergio
authors.initials: S
authors.lastname: Moreno
authors.forename: Angeles
authors.initials: A
authors.lastname: Almeida
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D064200:Cdh1 Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000201:enzymology / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D009929:Organ Size
chemical_list: D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; C577585:Fzr1 protein, mouse; D064173:Anaphase-Promoting Complex-Cyclosome