PMID- 34381067 OWN - NLM STAT- MEDLINE DCOM- 20211112 LR - 20240506 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 11 IP - 1 DP - 2021 Aug 11 TI - The zinc finger/RING domain protein Unkempt regulates cognitive flexibility. PG - 16299 LID - 10.1038/s41598-021-95286-y [doi] LID - 16299 AB - Correct orchestration of nervous system development is a profound challenge that involves coordination of complex molecular and cellular processes. Mechanistic target of rapamycin (mTOR) signaling is a key regulator of nervous system development and synaptic function. The mTOR kinase is a hub for sensing inputs including growth factor signaling, nutrients and energy levels. Activation of mTOR signaling causes diseases with severe neurological manifestations, such as tuberous sclerosis complex and focal cortical dysplasia. However, the molecular mechanisms by which mTOR signaling regulates nervous system development and function are poorly understood. Unkempt is a conserved zinc finger/RING domain protein that regulates neurogenesis downstream of mTOR signaling in Drosophila. Unkempt also directly interacts with the mTOR complex I component Raptor. Here we describe the generation and characterisation of mice with a conditional knockout of Unkempt (Unk(cKO)) in the nervous system. Loss of Unkempt reduces Raptor protein levels in the embryonic nervous system but does not affect downstream mTORC1 targets. We also show that nervous system development occurs normally in Unk(cKO) mice. However, we find that Unkempt is expressed in the adult cerebellum and hippocampus and behavioural analyses show that Unk(cKO) mice have improved memory formation and cognitive flexibility to re-learn. Further understanding of the role of Unkempt in the nervous system will provide novel mechanistic insight into the role of mTOR signaling in learning and memory. CI - (c) 2021. The Author(s). FAU - Vinsland, Elin AU - Vinsland E AD - Maurice Wohl Clinical Neuroscience Institute, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK. AD - Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solnavagen 9, 17177, Stockholm, Sweden. FAU - Baskaran, Pranetha AU - Baskaran P AD - Maurice Wohl Clinical Neuroscience Institute, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK. FAU - Mihaylov, Simeon R AU - Mihaylov SR AD - Maurice Wohl Clinical Neuroscience Institute, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK. FAU - Hobbs, Carl AU - Hobbs C AD - Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, SE1 1UL, UK. FAU - Wood, Hannah AU - Wood H AD - Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, 16 De Crespigny Park, London, PO82SE5 8AF, UK. FAU - Bouybayoune, Ihssane AU - Bouybayoune I AD - Centre for Developmental Neurobiology and MRC Centre for Neurodevelopmental Disorders, King's College London, New Hunt's House, Guy's Campus, London, SE1 1UL, UK. FAU - Shah, Kriti AU - Shah K AD - Department of Biochemistry, University of California, Riverside, 3401 Watkins Drive, Boyce Hall 1415A - MURN, Riverside, CA, 92521, USA. FAU - Houart, Corinne AU - Houart C AD - Centre for Developmental Neurobiology and MRC Centre for Neurodevelopmental Disorders, King's College London, New Hunt's House, Guy's Campus, London, SE1 1UL, UK. FAU - Tee, Andrew R AU - Tee AR AD - Cancer and Genetics Building, Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park Way, Cardiff, CF14 4XN, UK. FAU - Murn, Jernej AU - Murn J AD - Department of Biochemistry, University of California, Riverside, 3401 Watkins Drive, Boyce Hall 1415A - MURN, Riverside, CA, 92521, USA. FAU - Fernandes, Cathy AU - Fernandes C AD - Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, 16 De Crespigny Park, London, PO82SE5 8AF, UK. AD - MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 4th Floor, New Hunt's House, London, SE1 1UL, UK. FAU - Bateman, Joseph M AU - Bateman JM AD - Maurice Wohl Clinical Neuroscience Institute, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK. joseph_matthew.bateman@kcl.ac.uk. LA - eng GR - 100160/Z/12/Z/WT_/Wellcome Trust/United Kingdom GR - MR/T033126/1/MRC_/Medical Research Council/United Kingdom GR - MR/W006251/1/MRC_/Medical Research Council/United Kingdom GR - 200668/Z/16/Z/WT_/Wellcome Trust/United Kingdom GR - MR/N026063/1/MRC_/Medical Research Council/United Kingdom GR - WT_/Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20210811 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (DNA-Binding Proteins) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) SB - IM MH - Animals MH - Cerebellum/metabolism MH - Cognition/*physiology MH - DNA-Binding Proteins/*metabolism MH - Drosophila/metabolism MH - HeLa Cells MH - Hippocampus/metabolism MH - Humans MH - Malformations of Cortical Development/*metabolism MH - Mechanistic Target of Rapamycin Complex 1/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Neurogenesis/physiology MH - Signal Transduction/physiology MH - Zinc Fingers/*physiology PMC - PMC8357790 COIS- The authors declare no competing interests. EDAT- 2021/08/13 06:00 MHDA- 2021/11/16 06:00 PMCR- 2021/08/11 CRDT- 2021/08/12 05:58 PHST- 2021/03/10 00:00 [received] PHST- 2021/07/21 00:00 [accepted] PHST- 2021/08/12 05:58 [entrez] PHST- 2021/08/13 06:00 [pubmed] PHST- 2021/11/16 06:00 [medline] PHST- 2021/08/11 00:00 [pmc-release] AID - 10.1038/s41598-021-95286-y [pii] AID - 95286 [pii] AID - 10.1038/s41598-021-95286-y [doi] PST - epublish SO - Sci Rep. 2021 Aug 11;11(1):16299. doi: 10.1038/s41598-021-95286-y.