{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T10:13:06Z","timestamp":1766139186131,"version":"3.41.2"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Foxr1 is a member of the evolutionarily conserved forkhead box (Fox) family of transcription factors, characterized by a winged-helix DNA-binding domain. We previously demonstrated that <jats:italic>Foxr1<\/jats:italic> deletion in mice results in severe perinatal lethality, cortical thinning, and ventricular enlargement, indicating its essential role in survival and brain development. Here, we extend these findings by showing that <jats:italic>Foxr1<\/jats:italic> knockout mice develop microcephaly accompanied by cortical and hippocampal hypoplasia at postnatal day 0 (P0). Cortical thinning is primarily driven by a significant reduction in layer 2\/3 neurons, linked to impaired generation of later-born neurons. This reduction correlates with decreased proliferation of progenitors (Ki67- and Tbr2-positive cells) at embryonic day 16.5 (E16.5), a critical period for upper-layer neurogenesis. In the hippocampus, <jats:italic>Foxr1<\/jats:italic> knockouts exhibit reduced area, and cell counts at P0, accompanied by increased proliferation (Ki67-positive cells), and elevated apoptosis (CC3-positive) at E16.5, suggesting broader disruptions in progenitor maintenance. Together, these findings suggest Foxr1 is an important regulator of progenitor dynamics and neuron production in cortical and hippocampal development.<\/jats:p>","DOI":"10.3389\/fnins.2025.1589043","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T05:23:44Z","timestamp":1748323424000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Foxr1 deletion causes microcephaly and leads to cortical and hippocampal hypoplasia"],"prefix":"10.3389","volume":"19","author":[{"given":"Hannah","family":"Waxman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"Kankkunen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arya","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margo","family":"Dowgiewicz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uwe","family":"Beffert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Ho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"ref1","first-page":"1","article-title":"Time of neuron origin in the hippocampal region. An autoradiographic study in the mouse","volume":"2","author":"Angevine","year":"1965","journal-title":"Exp. Neurol. Suppl."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1002\/cne.901900107","article-title":"Development of the hippocampal region in the rat I. Neurogenesis examined with 3H-thymidine autoradiography","volume":"190","author":"Bayer","year":"1980","journal-title":"J. Comp. Neurol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"909","DOI":"10.3390\/brainsci10120909","article-title":"Differential timing and coordination of neurogenesis and astrogenesis in developing mouse hippocampal subregions","volume":"10","author":"Bond","year":"2020","journal-title":"Brain Sci."},{"key":"ref4","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/978-1-0716-3437-0_33","article-title":"Automated cell counting of macrophages in situ","volume-title":"Tissue-resident macrophages: methods and protocols","author":"Bouadi","year":"2024"},{"key":"ref5","unstructured":"AutoMorFi: automated whole-image morphometry in Fiji\/ImageJ for diverse analyses and discoveries\n          \n          \n            \n              Bouadi\n              O.\n            \n            \n              Yao\n              C.\n            \n            \n              Zeng\n              J.\n            \n            \n              Beason\n              D.\n            \n            \n              Inda\n              N.\n            \n            \n              Malone\n              Z.\n            \n          \n          \n          2024"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1002\/cne.901510203","article-title":"Time of neuron origin in the hippocampus and dentate gyrus of normal and reeler mutant mice: an autoradiographic analysis","volume":"151","author":"Caviness","year":"1973","journal-title":"J. Comp. Neurol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1177\/0192623317728134","article-title":"Histology atlas of the developing prenatal and postnatal mouse central nervous system, with emphasis on prenatal days E7.5 to E18.5","volume":"45","author":"Chen","year":"2017","journal-title":"Toxicol. Pathol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e5534","DOI":"10.7717\/peerj.5534","article-title":"foxr1 is a novel maternal-effect gene in fish that is required for early embryonic success","volume":"6","author":"Cheung","year":"2018","journal-title":"PeerJ"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"611841","DOI":"10.3389\/fncir.2020.611841","article-title":"Origins, development, and compartmentation of the granule cells of the cerebellum","volume":"14","author":"Consalez","year":"2021","journal-title":"Front. Neural Circuits"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1152\/physrev.00044.2020","article-title":"How development sculpts hippocampal circuits and functions","volume":"102","author":"Cossart","year":"2022","journal-title":"Physiol. Rev."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1016\/j.bcp.2012.10.013","article-title":"Targeting FOXM1 in cancer","volume":"85","author":"Halasi","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"463","DOI":"10.3892\/IJMM.14.3.463","article-title":"Germ-line mutation of Foxn5 gene in mouse lineage","volume":"14","author":"Katoh","year":"","journal-title":"Int. J. Mol. Med."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.3892\/ijo.24.5.1339","article-title":"Identification and characterization of human FOXN5 and rat Foxn5 genes in silico","volume":"24","author":"Katoh","year":"","journal-title":"Int. J. Oncol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"2439","DOI":"10.1093\/cercor\/bhn260","article-title":"Intermediate neuronal progenitors (basal progenitors) produce pyramidal-projection neurons for all layers of cerebral cortex","volume":"19","author":"Kowalczyk","year":"2009","journal-title":"Cereb. Cortex"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1093\/MOLBEV\/MSN047","article-title":"Genesis and expansion of metazoan transcription factor gene classes","volume":"25","author":"Larroux","year":"2008","journal-title":"Mol. Biol. Evol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1038\/NATURE03649","article-title":"The initiation of liver development is dependent on Foxa transcription factors","volume":"435","author":"Lee","year":"2005","journal-title":"Nature"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"775","DOI":"10.15252\/msb.20145504","article-title":"Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes","volume":"11","author":"Li","year":"2015","journal-title":"Mol. Syst. Biol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e1009854","DOI":"10.1371\/journal.pgen.1009854","article-title":"FOXR1 regulates stress response pathways and is necessary for proper brain development","volume":"17","author":"Mota","year":"2021","journal-title":"PLoS Genet."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1002\/(SICI)1096-9861(19970818)385:1<95:AID-CNE6>3.0.CO;2-7","article-title":"The timetable of laminar neurogenesis contributes to the specification of cortical areas in mouse isocortex","volume":"385","author":"Polleux","year":"1997","journal-title":"J. Comp. Neurol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1038\/nn1694","article-title":"The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells","volume":"9","author":"Shen","year":"2006","journal-title":"Nat. Neurosci."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"10357","DOI":"10.1523\/JNEUROSCI.19-23-10357.1999","article-title":"Sequence of neuron origin and neocortical laminar fate: relation to cell cycle of origin in the developing murine cerebral wall","volume":"19","author":"Takahashi","year":"1999","journal-title":"J. Neurosci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/0092-8674(89)90133-5","article-title":"The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo","volume":"57","author":"Weigel","year":"1989","journal-title":"Cell"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"E2714","DOI":"10.1073\/pnas.1310233110","article-title":"Axon position within the corpus callosum determines contralateral cortical projection","volume":"110","author":"Zhou","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1589043\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T05:23:46Z","timestamp":1748323426000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1589043\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,27]]},"references-count":23,"alternative-id":["10.3389\/fnins.2025.1589043"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2025.1589043","relation":{},"ISSN":["1662-453X"],"issn-type":[{"type":"electronic","value":"1662-453X"}],"subject":[],"published":{"date-parts":[[2025,5,27]]},"article-number":"1589043"}}