Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.
Emily BanksVincent FrancisSheng-Jia LinFares KharfallahVladimir S FonovMaxime LévesqueChanshuai HanGopinath KulasekaranMarius TuznikArmin BayatiReem A AlkhaterFowzan Sami AlkurayaLoukas ArgyriouMeisam BabaeiMelanie BahloBehnoosh BakhshoodehEileen BarrLauren BartikMahmoud BassionyMiriam BertrandDominique BraunRebecca BuchertMauro BudettaMaxime Cadieux-DionDaniel G CalameHeidi CopeDonna CushingStephanie EfthymiouMarwa Abd ElmaksoudHuda G El SaidTawfiq FroukhHarinder K GillJoseph G GleesonLaura GogollElaine Suk-Ying GohVykuntaraju K GowdaTobias B HaackMais O HashemStefan HauserTrevor L HoffmanJacob S HogueAkimoto HosokawaHenry HouldenKevin HuangStephanie HuynhEhsan G KarimianiSilke KaulfußG Christoph KorenkeAmy KritzerHane LeeJames R. LupskiElysa J MarcoKirsty McWalterArakel MinassianBerge A MinassianDavid MurphyJuanita Neira-FresnedaHope NorthrupDenis M NyagaBarbara Oehl-JaschkowitzMatthew OsmondRichard PersonDavut PehlivanCassidy PetreeLynette G SadleirCarol J SaundersLudger SchoelsVandana ShashiRebecca C SpillmannVarunvenkat M SrinivasanParia N TorbatiTulay Tosnull nullMaha Saad ZakiDihong ZhouChristiane ZweierJean-François TrempeThomas M DurcanZiv Gan OrMassimo AvoliCesar AlvesGuarav K VarshneyReza MaroofianDavid A RudkoPeter S McPhersonPublished in: Nature communications (2024)
Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.
Keyphrases
- induced pluripotent stem cells
- induced apoptosis
- endothelial cells
- cell cycle arrest
- single cell
- cell therapy
- primary care
- machine learning
- stem cells
- spinal cord
- copy number
- pluripotent stem cells
- gene expression
- early onset
- endoplasmic reticulum stress
- deep learning
- signaling pathway
- white matter
- mesenchymal stem cells
- case report
- small molecule
- resting state
- multiple sclerosis
- subarachnoid hemorrhage
- protein protein