X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons
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...
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Published in | Cellular and molecular life sciences : CMLS Vol. 78; no. 21-22; pp. 7043 - 7060 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Cham
Springer International Publishing
01.11.2021
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | 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 17β-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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1420-682X 1420-9071 |
DOI: | 10.1007/s00018-021-03945-0 |