Sex differences in expression of transforming growth factor-alpha and epidermal growth factor receptor mRNA in Waved-1 and C57Bl6 mice.

A reduction of transforming growth factor-alpha (TGFalpha) expression in the spontaneous Waved-1 (Wa-1) mutant mouse causes specific behavioral and anatomical changes, including reduced fear learning and stress response and enlarged lateral ventricles. These alterations are observed predominantly in male Wa-1 mice after puberty. We hypothesized that regional differences in the expression of TGFalpha and its receptor, epidermal growth factor receptor (EGFR), may regulate the sexual dimorphism of the brain structures and functions during postnatal development. In general, fear learning-associated structures, including hippocampus and amygdala, showed maximum expression before puberty, regardless of genotype. In contrast, an overall temporal delay in the rise of both transcript levels, which peaked around or after puberty onset, was observed for the major stress regulatory hypothalamo-pituitary-adrenal axis. This pattern of expression was reversed for amygdala EGFR and hypothalamus TGFalpha and EGFR transcripts in males. When regional TGFalpha expression was compared between control and Wa-1 mice, far more complex patterns than expected were observed that revealed sex- and structure-dependent differences. In fact, the amygdala, hypothalamus, and pituitary TGFalpha expression pattern in Wa-1 exhibited a clear sex dependency across various age groups. Surprisingly, there was no compensatory up-regulation of the EGFR transcript in Wa-1 mice. The observed expression patterns of the TGFalpha signaling system during normal development and in the Wa-1 mutant mouse suggest complex sex- and age-dependent transcription regulatory mechanisms.