Pituitary hormones as neurotrophic signals: Update on hypothalamic differentiation in genetic models of altered feedback

Studies of mutant mice that are growth hormone (GH)- and prolactin (PRL)def icient have provided evidence that these pituitary hormones have trophic, a s well as dynamic, feedback effects on the hypothalamic neurons that regula te GH and PRL secretion (1). This review examines further evidence, from th ose animals and from recent transgenic models, for GH and PRL effects on ne uronal differentiation. Characterization of the Ames dwarf (Prop-1[df]) mut ation and discovery of other genes important to pituitary differentiation r eveal an expression sequence of transcription factors, Hesx1 (Rpx) to P-Lim to Prop-1 to Pit-1, that heralds influence on hypothalamic differentiation . Occasional expression of GH and PRL in the Ames dwarf pituitary may resul t from the "partial loss of function" nature of the Ames Prop-1 mutation. I n transgenic mice with moderately or extremely elevated GH levels, neurons that regulate GH exhibit respective maximum and minimum expression and cell number in inhibitory somatostatin (SRIH) and in stimulatory OR-releasing h ormone (GHRH). The phenomenon is inverted in OR-lacking dwarfs, and pattern s of SRIH underexpression and GHRH overexpression are established early in postnatal development. The differentiation of PRL-inhibiting dopaminergic ( DA) neurons is supported not only by PRL, but by human GH, which is lactoge nic in rodents. Transgenic mice with peripherally expressed hGH have increa sed numbers of DA neurons, as opposed to the decreased DA population in PRL -deficient dwarf mice. Rats engineered to express hGH in GHRH neurons do no t show this increase, whereas spontaneously GH-deficient dwarf rats show in creased DA neuron number. These findings may be explained by feedback on ne urons that co-express GHRH and DA. Current studies suggest that Snell (Pit- 1[dw]) dwarf mice show a more severe and earlier DA neuron deficiency than Ames dwarfs, and that PRL feedback must occur prior to 20 days of postnatal age to maintain the DA neuronal phenotype. Insights into the mechanisms of GH and PRL effects on hypophysiotropic neurons include receptor localizati on on identified neuronal phenotypes, including intermediate neurons that m ediate dynamic feedback, and elucidation of signal transduction pathways fo r GH and PRL in peripheral cell types. New transgenic models of altered GH, PRL, or receptor expression offer further study of neurotrophic effects.