X-linked histone demethylase kdm6a as a candidate to mediate sex chromosome effects on Ngn3 dimorphic expression in the developing brain

CABRERA ZAPATA, L.E.; AREVALO, M.A.; GARCIA-SEGURA, L.M.; CAMBIASSO, M.J.

Santiago de Compostela, España

Congreso; 18th National Meeting of the Spanish Society of Neuroscience (SENC); 2019

Spanish Society of Neuroscience

Several X-linked genes are involved in neuronalgrowth and differentiation and may contribute to the generation of sexdifferences in brain. Previous results showed that XX hypothalamic neurons grow at a faster rate of development and exhibit higherexpression of the neuritogenic gen neurogenin3 (Ngn3) than XY neurons, independently of gonadal hormones.Since Ngn3 is an autosomal gene, suchsex differences should be consequence of differences in the expression of X or Ychromosome genes. Using the Four CoreGenotypes mouse model, we analyzed the expression of X-linked genes involved in neuronal development which are probablecandidates to regulate Ngn3 and otherneuritogenic genes. We evaluated by RT-qPCR the expression of Ddx3x, Eif2s3x, Kdm5c, Kdm6a, Syp, Mecp2 and Usp9x in primary hypothalamic culturesfrom E15 embryos segregated by gonadal sex and genotype. Ddx3x, Eif2s3x and Kdm6a showed higher levels of expressionin XX than in XY neurons (p<0.05), regardless of gonadal type. Since Kdm6a is ahistone demethylase that regulates autosomal gene transcription, we decided tofocus our study on it. Exogenous administration of 17β-estradiol (10-10M) did not affect Kdm6a expression inXX/XY neuronal cultures. Moreover, the expression pattern of Kdm6a mRNA in ventromedial hypothalamicregion varied with age: only XX malesshowed higher levels of Kdm6a thanthe other genotypes in hypothalami of adults. Finally, we evaluated the effectof Kdm6a/b activity inhibitor GSK-J4 on the sexually dimorphic expression of Ngn3. Our results indicated that GSK-J4diminished Ngn3 expression only in XX neurons, independently of gonadaltype. Altogether, these results point to Kdm6a as a regulator of Ngn3, andencourage to continuing with further experiments in order to better understandits role in the generation of sex differences in the developing brain.                                                                                                                                                 Financial support: CONICET, ANPCyT, andSECyT-UNC, Argentina; BFU2017-82754-R and MHE-200057, Spain.