X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons
| Autor: | María Julia Cambiasso, Camila Sosa, María Ángeles Arévalo, Lucas Ezequiel Cabrera Zapata, Luis M. Garcia-Segura, Carla D. Cisternas |
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| Přispěvatelé: | Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina), Agencia Nacional de Promoción Científica y Tecnológica (Argentina), Universidad Nacional de Córdoba (Argentina), Agencia Estatal de Investigación (España), European Commission, International Brain Research Organization, International Society for Neurochemistry, Federación Española de Enfermedades Raras |
| Rok vydání: | 2021 |
| Předmět: |
Male
Sex Differentiation Transgene Period (gene) Hypothalamus Nerve Tissue Proteins Biology Histones Ngn3 Cellular and Molecular Neuroscience Mice Genes X-Linked Gene expression Sex differences Animals Hypothalamic neurons Molecular Biology Gene Neuritogenesis Pharmacology Histone Demethylases Neurons Sex Characteristics Kdm6a Cell Biology Axons H3K27 demethylation Cell biology NEUROD2 NEUROD1 biology.protein Molecular Medicine Demethylase Female Original Article |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Cellular and Molecular Life Sciences |
| Popis: | Several X-linked genes are involved in neuronal differentiation and may contribute to the generation of sex dimorphisms in the brain. Previous results showed that XX hypothalamic neurons grow faster, have longer axons, and exhibit higher expression of the neuritogenic gene neurogenin 3 (Ngn3) than XY before perinatal masculinization. Here we evaluated the participation of candidate X-linked genes in the development of these sex differences, focusing mainly on Kdm6a, a gene encoding for an H3K27 demethylase with functions controlling gene expression genome-wide. We established hypothalamic neuronal cultures from wild-type or transgenic Four Core Genotypes mice, a model that allows evaluating the effect of sex chromosomes independently of gonadal type. X-linked genes Kdm6a, Eif2s3x and Ddx3x showed higher expression in XX compared to XY neurons, regardless of gonadal sex. Moreover, Kdm6a expression pattern with higher mRNA levels in XX than XY did not change with age at E14, P0, and P60 in hypothalamus or under 17ß-estradiol treatment in culture. Kdm6a pharmacological blockade by GSK-J4 reduced axonal length only in female neurons and decreased the expression of neuritogenic genes Neurod1, Neurod2 and Cdk5r1 in both sexes equally, while a sex-specific effect was observed in Ngn3. Finally, Kdm6a downregulation using siRNA reduced axonal length and Ngn3 expression only in female neurons, abolishing the sex differences observed in control conditions. Altogether, these results point to Kdm6a as a key mediator of the higher axogenesis and Ngn3 expression observed in XX neurons before the critical period of brain masculinization. This study was supported by grants from Argentina: Consejo Nacional de Investigaciones Científcas y Técnicas (CONICET, PUE 2016 No. 22920160100135CO), Agencia Nacional de Promoción Científca y Tecnológica (ANPCyT, PICT 2015 No. 1333 and PICT 2019 No. 2176), and Secretaría de Ciencia y Tecnología de la Universidad Nacional de Córdoba (SECyT-UNC, 2018–2021) to MJC, from Spain: Agencia Estatal de Investigacion (AEI) co-funded by FEDER (BFU2017-82754-R and PID2020-115019RBI00) to MAA and LMGS and the Enhancing Mobility between Latin America, Caribbean and the European Union in Health & Environment (EMHE)-CSIC Program (MHE-200057) to LMGS and MJC, and from international organizations: International Brain Research Organization (IBRO) Return Home Fellowship and International Society for Neurochemistry (ISN) and Committee for Aid and Education in Neurochemistry (CAEN) Grant to CDC. |
| Databáze: | OpenAIRE |
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