MECHANISMS OF ESTROGEN ACTION DURING NEURAL DEVELOPMENT - MEDIATION BY INTERACTIONS WITH THE NEUROTROPHINS AND THEIR RECEPTORS

Estrogen enhances the growth and differentiation of neurites within th e developing forebrain. A critical issue is whether these developmenta l actions of estrogen are mediated directly or indirectly by means of autocrine responses or local paracrine mechanisms, through interaction s with growth factors, such as the neurotrophins, and their receptors. Support for the latter hypothesis comes from our recent observations of co-expression of estrogen receptor mRNA with the mRNAs for the neur otrophins and their receptors; differential and reciprocal up-regulati on of estrogen and NGF receptor mRNA and protein expression by estroge n in adult female rat sensory neurons, PC12 cells; and cerebral cortic al cultures; and putative estrogen response elements in the NGF, BDNF, trkA and p75 genes. Estrogen and the neurotrophins may influence each other's actions by regulating receptor and ligand availability or by reciprocal regulation at the level of signal transduction or gene tran scription. The neurotrophins may serve as regulatory ''switches'' for the apparent developmentally-regulated, differential pattern of estrog en receptor regulation by its ligand, whereby their ability to increas e estrogen receptor levels significantly may be sufficient to override the intrinsic suppressive action of estrogen on its receptor. Estroge n and the neurotrophins, acting in concert and reciprocally, may stimu late the synthesis of proteins required for neuronal differentiation, survival and maintenance of function.