Microarray analysis of neonatal rat anteroventral periventricular transcriptomes identifies the proapoptotic Cugbp2 gene as sex-specific and regulated by estradiol

Neuroscience. 2015 Sep 10;303:312-22. doi: 10.1016/j.neuroscience.2015.07.008. Epub 2015 Jul 9.


Sexually dimorphic neural structures regulate numerous gender-specific functions including luteinizing hormone (LH) release patterns. The female cyclic surge pattern of release is controlled by the anteroventral periventricular nucleus (AVPV), a preoptic area (POA) region that is significantly smaller in males. The prevailing hypothesis used to explain these differences in structure and function is that a "default" feminine AVPV is defeminized by exposure to estradiol (E2), a metabolite of testosterone (T) produced by the perinatal testes. E2 exposure then culminates in apoptosis in the male AVPV, but the upstream pathways are poorly understood. To address this issue, we compared AVPV transcriptomes of postnatal day 2 (PND2) males and females with those of females treated with E2 or vehicle. Only six of 89 sex-specific genes were also regulated by E2 in the PND2 AVPV and E2 regulated over 280 genes not found to be sex-specific. Of targets that changed similarly in males and E2-treated females, the gene encoding CUG triplet repeat, RNA-binding protein 2 (Cugbp2), a proapoptotic protein, showed the highest fold-changes. Quantitative polymerase chain reaction (QPCR) studies confirmed higher mRNA levels in PND2 male and E2-treated female AVPVs wherein E2 induces apoptosis. POA mapping studies detected Cugbp2 mRNA in the AVPV and in the sexually dimorphic nucleus of the POA (SDN-POA); however, sex differences and E2 effects occurred only in the AVPV. Combined with evidence that Cugbp2 regulates splicing and translation of mRNAs linked to sexual differentiation, we propose that this gene mediates E2-dependent effects on AVPV defeminization.

Keywords: anteroventral periventricular nucleus; estradiol; luteinizing hormone; sexual differentiation; transcriptome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • CELF Proteins / genetics
  • CELF Proteins / metabolism*
  • Estradiol / pharmacology*
  • Female
  • Gene Expression Regulation, Developmental / drug effects*
  • Hypothalamus, Anterior* / drug effects
  • Hypothalamus, Anterior* / growth & development
  • Hypothalamus, Anterior* / metabolism
  • Male
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Pregnancy
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA / genetics
  • Receptors, GABA / metabolism
  • Receptors, Glutamate / genetics
  • Receptors, Glutamate / metabolism
  • Sex Differentiation*
  • Transcriptome / drug effects
  • Transcriptome / physiology


  • CELF Proteins
  • Celf2 protein, rat
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Receptors, GABA
  • Receptors, Glutamate
  • Estradiol