Abstract
The hypothalamus contains nuclei and cell populations that are critical in reproduction and that differ significantly between the sexes in structure and function. To examine the molecular and genetic basis for these differences, we quantified gene expression in the hypothalamus of 39 pairs of adult male and female mice belonging to the BXD strains. This experimental design enabled us to define hypothalamic gene coexpression networks and provided robust estimates of absolute expression differences. As expected, sex has the strongest effect on the expression of genes on the X and Y chromosomes (e.g., Uty, Xist, Kdm6a). Transcripts associated with the endocrine system and neuropeptide signaling also differ significantly. Sex-differentiated transcripts often have well delimited expression within specific hypothalamic nuclei that have roles in reproduction. For instance, the estrogen receptor (Esr1) and neurokinin B (Tac2) genes have intense expression in the medial preoptic and arcuate nuclei and comparatively high expression in females. Despite the strong effect of sex on single transcripts, the global pattern of covariance among transcripts is well preserved, and consequently, males and females have well matched coexpression modules. However, there are sex-specific hub genes in functionally equivalent modules. For example, only in males is the Y-linked gene, Uty, a highly connected transcript in a network that regulates chromatin modification and gene transcription. In females, the X chromosome paralog, Kdm6a, takes the place of Uty in the same network. We also find significant effect of sex on genetic regulation and the same network in males and females can be associated with markedly different regulatory loci. With the exception of a few sex-specific modules, our analysis reveals a system in which sets of functionally related transcripts are organized into stable sex-independent networks that are controlled at a higher level by sex-specific modulators.
Highlights
The hypothalamus controls many facets and phases of reproductive behavior
We report the linkages as likelihood ratio statistic (LRS) scores (LOD score = LRS/4.61)
SEX DIFFERENCE IN GENE EXPRESSION IN THE HYPOTHALAMUS A set of 48 transcripts and cognate genes in the hypothalamus differ significantly in expression between the sexes at an false discovery rate (FDR) threshold of 0.1 (Table 1). Thirteen of these are located on the sex Chrs and 35 are located on autosomes
Summary
The hypothalamus controls many facets and phases of reproductive behavior. Several sub-nuclei and regions within the hypothalamus differ significantly between males and females. Sex-dependent variation in brain structure and function is triggered mainly by genes linked to the sex chromosomes (Chrs) and to the downstream effects of gonadal hormones Apart from these proximal causes, another layer of influence on sexual differentiation comes from widespread sequence variants distributed across the entire genome. In mice, a sexually dimorphic preoptic nucleus in the DBA/2J strain is undetectable in the C57BL/6J strain (Brown et al, 1999; Mathieson et al, 2000) Such global strain-dependent effects on brain differentiation suggest that there is significant interplay between the sex determinants and autosomal genotype. These autosomal modulators of sex differences likely contribute to the many sex-specific quantitative trait loci (QTLs) that influence a large number of behavioral, physiological, and molecular traits (Melo et al, 1996; Weiss et al, 2006; Bhasin et al, 2008; van Nas et al, 2009)
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