biostudies-literatureShimaoka KMEXT | Japan Society for the Promotion of ScienceMEXT | Japan Society for the Promotion of Science (JSPS)Tokumori Yasumoto Memorial TrustNational Center of Neurology and PsychiatryJapan Agency for Medical Research and DevelopmentJapan Health Research Promotion BureauJapan Health Research Promotion Bureau (JH)Multilayered Stress DiseasesNational Center of Neurology and Psychiatry (NCNP)Japan Agency for Medical Research and Development (AMED)1354-1378https://www.ebi.ac.uk/biostudies/studies/S-EPMC11876313biostudies-literatureUnknown44(5)AUTS2 syndrome is characterized by intellectual disability and microcephaly, and is often associated with autism spectrum disorder, but the underlying mechanisms, particularly concerning microcephaly, remain incompletely understood. Here, we analyze mice mutated for the transcriptional regulator AUTS2, which recapitulate microcephaly. Their brains exhibit reduced division of intermediate progenitor cells (IPCs), leading to fewer neurons and decreased thickness in the upper-layer cortex. Increased expression of the AUTS2 transcriptional target Robo1 in the mutant animals suppresses IPC division, and transcriptomic and chromatin profiling shows that AUTS2 primarily represses transcription of genes like Robo1 in IPCs. Regions around the transcriptional start sites of AUTS2 target genes are enThe EMBO journalThe microcephaly-associated transcriptional regulator AUTS2 cooperates with Polycomb complex PRC2 to produce upper-layer neurons in mice.PMC1187631324ek0109764h0001JP16H065316-92024-D-0124wm0625508h0001JPMXP1323015483JP22H0273024wm0425005h00044-52020-B-074-6JP22K15134Go YInoue TMiyashita SHori KSakamoto AEgusa SFTatsumoto SYamashiro KInoue YUImamura TAbe MTabe NKNHoshino MShimaoka KHasegawa INishitani KSakimura KfalseThe microcephaly-associated transcriptional regulator AUTS2 cooperates with Polycomb complex PRC2 to produce upper-layer neurons in mice.AUTS2 syndrome is characterized by intellectual disability and microcephaly, and is often associated with autism spectrum disorder, but the underlying mechanisms, particularly concerning microcephaly, remain incompletely understood. Here, we analyze mice mutated for the transcriptional regulator AUTS2, which recapitulate microcephaly. Their brains exhibit reduced division of intermediate progenitor cells (IPCs), leading to fewer neurons and decreased thickness in the upper-layer cortex. Increased expression of the AUTS2 transcriptional target Robo1 in the mutant animals suppresses IPC division, and transcriptomic and chromatin profiling shows that AUTS2 primarily represses transcription of genes like Robo1 in IPCs. Regions around the transcriptional start sites of AUTS2 target genes are en2025-01-01T00:00:00Z2025 Mar2026-06-01T22:05:03.257Z2025-04-04T13:46:37.577ZS-EPMC118763133981500510.1038/s44318-024-00343-7