Focal Adhesion Kinase and Paxillin: Novel Regulators of Brain Sexual Differentiation?

Abstract

Steroid-mediated sexual differentiation of the brain is a developmental process that permanently organizes the brain into a male or female phenotype. Previous studies in the rodent have examined the steroid-mediated mechanisms of male brain development. In an effort to identify molecules involved in female brain development, a high-throughput proteomics approach called PowerBlot was used to identify signaling proteins differentially regulated in the neonatal male and female rat hypothalamus during the critical period for brain sexual differentiation. Focal adhesion kinase (FAK) and paxillin, both members of the focal adhesion complex family of proteins, were significantly elevated in the newborn female compared with the male hypothalamus. Sex differences in these proteins were not detected in brain regions that are not subject to substantial organizational effects of steroids. Estrogens, the aromatized products of testosterone in the male, can both masculinize and defeminize the male brain. Daily estradiol administration to neonatal females significantly reduced FAK and paxillin in the hypothalamus, and aromatase inhibition increased paxillin in males to levels comparable with females. Androgens also appear to modulate paxillin levels in combination with estrogen action. Across development, hypothalamic levels of FAK were significantly elevated in females compared with males on postnatal d 6. Synaptic circuits in the hypothalamus develop sex differences perinatally. Estradiol treatment of cultured hypothalamic neurons significantly enhanced axon branching (P<0.01), consistent with the phenotype of FAK-deficient neurons. Together, these data implicate FAK and paxillin as regulators of sex differences in neuronal morphology.

Neonatal exposure to 17β-estradiol down-regulates the expression of synaptogenesis related genes in selected brain regions of adult female rats

“…[19]. FAK is generally high in the hypothalamus of neonatal female [35], and the decrease following estrogen treatment as is evident from the present results indicated that neonatal estradiol establishes irreversible masculinization and defeminization of the female rat brain. Granulin, a cytotropic factor was found to be increased in hypothalamus of male rats after neonatal estradiol treatment [36] but the significance of its increase in expression in POA in our study currently is not known.…”

Dose-related gene expression changes in forebrain following acute, low-level chlorpyrifos exposure in neonatal rats

“…Focal adhesions are multiprotein complexes that coordinate integrins, extracellular matrix proteins and the cytoskeleton (Harjanto and Zaman, 2010). Moreover, gender-selective differences in paxillin have been correlated with sexual differentiation in brain regions (e.g., hypothalamus) that develop perinatally in a sex-related manner (Speert et al, 2007). Some studies have reported gender-specific effects of early CPF exposures (Dam et al, 2000; Raines et al, 2001; Slotkin et al, 2001; Levin et al, 2001, 2002).…”

Neonatal Exposure to Diethylstilbestrol Alters Expression of DNA Methyltransferases and Methylation of Genomic DNA in the Mouse Uterus

“…Although intron 1 includes a few CpG islands, there are 2 CpG islands around spot U7 (about 200 bp upstream and 100 bp downstream). The relation between estrogen and paxillin is not clear, but there is a report that in the hypothalamus of neonatal female rat, esradiol administration reduced the expression of paxillin and affected the brain sexual differentiation [42]. On the other hand, there are no genes around spot 10.…”