PMID- 33762301 OWN - NLM STAT- MEDLINE DCOM- 20210702 LR - 20210702 IS - 2373-2822 (Electronic) IS - 2373-2822 (Linking) VI - 8 IP - 3 DP - 2021 May-Jun TI - Notch Signaling between Cerebellar Granule Cell Progenitors. LID - ENEURO.0468-20.2021 [pii] LID - 10.1523/ENEURO.0468-20.2021 [doi] AB - Cerebellar granule cells (GCs) are cells which comprise over 50% of the neurons in the entire nervous system. GCs enable the cerebellum to properly regulate motor coordination, learning, and consolidation, in addition to cognition, emotion and language. During GC development, maternal GC progenitors (GCPs) divide to produce not only postmitotic GCs but also sister GCPs. However, the molecular machinery for regulating the proportional production of distinct sister cell types from seemingly uniform GCPs is not yet fully understood. Here we report that Notch signaling creates a distinction between GCPs and leads to their proportional differentiation in mice. Among Notch-related molecules, Notch1, Notch2, Jag1, and Hes1 are prominently expressed in GCPs. In vivo monitoring of Hes1-promoter activities showed the presence of two types of GCPs, Notch-signaling ON and OFF, in the external granule layer (EGL). Single-cell RNA sequencing (scRNA-seq) and in silico analyses indicate that ON-GCPs have more proliferative and immature properties, while OFF-GCPs have opposite characteristics. Overexpression as well as knock-down (KD) experiments using in vivo electroporation showed that NOTCH2 and HES1 are involved cell-autonomously to suppress GCP differentiation by inhibiting NEUROD1 expression. In contrast, JAG1-expressing cells non-autonomously upregulated Notch signaling activities via NOTCH2-HES1 in surrounding GCPs, eventually suppressing their differentiation. These findings suggest that Notch signaling results in the proportional generation of two types of cells, immature and differentiating GCPs, which contributes to the well-organized differentiation of GCs. CI - Copyright (c) 2021 Adachi et al. FAU - Adachi, Toma AU - Adachi T AUID- ORCID: 0000-0002-1519-9310 AD - Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan. AD - Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, Japan. FAU - Miyashita, Satoshi AU - Miyashita S AUID- ORCID: 0000-0003-3421-2477 AD - Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan miyasatoshi@ncnp.go.jp hoshino@ncnp.go.jp. FAU - Yamashita, Mariko AU - Yamashita M AD - Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan. AD - Department of NCNP Brain Function and Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, TMDU, Tokyo 113-8510, Japan. FAU - Shimoda, Mana AU - Shimoda M AD - Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan. AD - Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, Japan. FAU - Okonechnikov, Konstantin AU - Okonechnikov K AUID- ORCID: 0000-0002-3409-2340 AD - Hopp-Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany. AD - Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. FAU - Chavez, Lukas AU - Chavez L AUID- ORCID: 0000-0002-8718-8848 AD - Department of Medicine, University of California San Diego, La Jolla, CA 92093. AD - Moores Cancer Center, University of California San Diego, La Jolla, CA 92093. FAU - Kool, Marcel AU - Kool M AD - Hopp-Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany. AD - Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. AD - Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands. FAU - Pfister, Stefan M AU - Pfister SM AD - Hopp-Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany. AD - Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. AD - Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany. FAU - Inoue, Takafumi AU - Inoue T AUID- ORCID: 0000-0002-2728-0060 AD - Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, Japan. FAU - Kawauchi, Daisuke AU - Kawauchi D AUID- ORCID: 0000-0002-1254-9725 AD - Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan. FAU - Hoshino, Mikio AU - Hoshino M AD - Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan miyasatoshi@ncnp.go.jp hoshino@ncnp.go.jp. LA - eng PT - Journal Article DEP - 20210512 PL - United States TA - eNeuro JT - eNeuro JID - 101647362 SB - IM MH - Animals MH - Cell Differentiation MH - *Cerebellum MH - Cytoplasmic Granules MH - Mice MH - *Signal Transduction MH - Stem Cells PMC - PMC8121261 OTO - NOTNLM OT - Notch signaling OT - cerebellar granule cell progenitor EDAT- 2021/03/26 06:00 MHDA- 2021/07/03 06:00 PMCR- 2021/05/08 CRDT- 2021/03/25 05:50 PHST- 2020/11/02 00:00 [received] PHST- 2021/03/03 00:00 [revised] PHST- 2021/03/09 00:00 [accepted] PHST- 2021/03/26 06:00 [pubmed] PHST- 2021/07/03 06:00 [medline] PHST- 2021/03/25 05:50 [entrez] PHST- 2021/05/08 00:00 [pmc-release] AID - ENEURO.0468-20.2021 [pii] AID - eN-CFN-0468-20 [pii] AID - 10.1523/ENEURO.0468-20.2021 [doi] PST - epublish SO - eNeuro. 2021 May 12;8(3):ENEURO.0468-20.2021. doi: 10.1523/ENEURO.0468-20.2021. Print 2021 May-Jun.