PMID- 34204880 OWN - NLM STAT- MEDLINE DCOM- 20210713 LR - 20211204 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 22 IP - 11 DP - 2021 Jun 3 TI - mTOR Driven Gene Transcription Is Required for Cholesterol Production in Neurons of the Developing Cerebral Cortex. LID - 10.3390/ijms22116034 [doi] LID - 6034 AB - Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders (ASD) to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy, and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood. Low levels of cholesterol are associated with a wide variety of neurodevelopmental disorders. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally regulated by mTOR complex 1 (mTORC1) signaling in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. We find that these genes are shared targets of the transcription factors SREBP, SP1, and NF-Y. Prenatal as well as postnatal mTORC1 inhibition downregulated expression of these genes which directly translated into reduced cholesterol levels, pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling. FAU - Schule, Martin AU - Schule M AUID- ORCID: 0000-0002-1677-0232 AD - Institute of Human Genetics, University Medical Center Mainz Johannes Gutenberg-University, 55131 Mainz, Germany. AD - Focus Program of Translational Neurosciences, University Medical Center Mainz, 55131 Mainz, Germany. FAU - Butto, Tamer AU - Butto T AUID- ORCID: 0000-0001-8028-0038 AD - Institute of Human Genetics, University Medical Center Mainz Johannes Gutenberg-University, 55131 Mainz, Germany. FAU - Dewi, Sri AU - Dewi S AUID- ORCID: 0000-0001-9849-3613 AD - Institute of Human Genetics, University Medical Center Mainz Johannes Gutenberg-University, 55131 Mainz, Germany. FAU - Schlichtholz, Laura AU - Schlichtholz L AD - Institute of Human Genetics, University Medical Center Mainz Johannes Gutenberg-University, 55131 Mainz, Germany. AD - Focus Program of Translational Neurosciences, University Medical Center Mainz, 55131 Mainz, Germany. FAU - Strand, Susanne AU - Strand S AD - First Department of Internal Medicine, University Medical Center Mainz, 55131 Mainz, Germany. FAU - Gerber, Susanne AU - Gerber S AUID- ORCID: 0000-0001-9513-0729 AD - Institute of Human Genetics, University Medical Center Mainz Johannes Gutenberg-University, 55131 Mainz, Germany. FAU - Endres, Kristina AU - Endres K AUID- ORCID: 0000-0002-1099-8287 AD - Department of Psychiatry and Psychotherapy, University Medical Center Johannes Gutenberg-University, 55131 Mainz, Germany. FAU - Schweiger, Susann AU - Schweiger S AD - Institute of Human Genetics, University Medical Center Mainz Johannes Gutenberg-University, 55131 Mainz, Germany. AD - Focus Program of Translational Neurosciences, University Medical Center Mainz, 55131 Mainz, Germany. AD - German Resilience Centre, University Medical Center Mainz, 55131 Mainz, Germany. FAU - Winter, Jennifer AU - Winter J AD - Institute of Human Genetics, University Medical Center Mainz Johannes Gutenberg-University, 55131 Mainz, Germany. AD - Focus Program of Translational Neurosciences, University Medical Center Mainz, 55131 Mainz, Germany. AD - German Resilience Centre, University Medical Center Mainz, 55131 Mainz, Germany. LA - eng GR - CRC1193/Deutsche Forschungsgemeinschaft/ PT - Journal Article DEP - 20210603 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (CCAAT-Binding Factor) RN - 0 (Sterol Regulatory Element Binding Proteins) RN - 97C5T2UQ7J (Cholesterol) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.- (Sp1 kinase) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Autophagy/genetics MH - CCAAT-Binding Factor/genetics MH - Cerebral Cortex/growth & development/metabolism MH - Cholesterol/biosynthesis/*genetics MH - Gene Expression Regulation, Developmental/genetics MH - Mechanistic Target of Rapamycin Complex 1/genetics MH - Mice MH - Neurogenesis/genetics MH - Neurons/*metabolism MH - Primary Cell Culture MH - Protein Kinases/*genetics MH - Signal Transduction/genetics MH - Sterol Regulatory Element Binding Proteins/*genetics MH - TOR Serine-Threonine Kinases/*genetics MH - Transcription, Genetic/genetics PMC - PMC8199781 OTO - NOTNLM OT - NF-Y OT - SP1 OT - SREBP OT - cholesterol OT - mTOR OT - mTORC1 OT - neurogenesis COIS- The authors declare no conflict of interest. EDAT- 2021/07/03 06:00 MHDA- 2021/07/14 06:00 PMCR- 2021/06/03 CRDT- 2021/07/02 01:22 PHST- 2021/04/21 00:00 [received] PHST- 2021/05/15 00:00 [revised] PHST- 2021/05/28 00:00 [accepted] PHST- 2021/07/02 01:22 [entrez] PHST- 2021/07/03 06:00 [pubmed] PHST- 2021/07/14 06:00 [medline] PHST- 2021/06/03 00:00 [pmc-release] AID - ijms22116034 [pii] AID - ijms-22-06034 [pii] AID - 10.3390/ijms22116034 [doi] PST - epublish SO - Int J Mol Sci. 2021 Jun 3;22(11):6034. doi: 10.3390/ijms22116034.