Postnatal Regression of Hypothalamic Dopaminergic Neurons in Prolactin-Deficient Snell Dwarf Mice

Abstract

AbstractBoth Snell (Pit-1dw or dwj, dw/dw) and Ames (Prophet of Pit-1df, df/df) dwarf mice fail to produce prolactin (PRL) as well as GH due to deficient transcription factor Pit-1 activity and have reduced numbers of hypothalamic PRL-inhibiting area A12 tuberoinfundibular dopaminergic (TIDA) neurons. It has been reported that the TIDA deficit in Ames dwarf mice develops postnatally as a reduction in number after an initial increase that is comparable to that of normal siblings. The present study was designed to characterize A12 TIDA neuronal development in the Snell dwarf (dw/dw) compared with littermate normal mice. Brains of normal (DW/?) and dwj/dwj mice were examined at 7, 14, 21, 30, and ≥ 60 postnatal days (d) by catecholamine fluorescence and quantification of neuron number after tyrosine hydroxylase immunostaining in dopaminergic (DA) areas A12, A13 (medial zona incerta), and A14 (periventricular nucleus). Fluorescence was less in dw/dw than in DW/? A12 perikarya and median eminence but was not reduced in other DA areas, such as substantia nigra, at all ages; A12 fluorescence was virtually absent in Snell dwarf adults. Numbers of TIDA neurons were comparable in normal and Snell dwarf mice at 7 d. In normal (DW/?) mice, A12 neurons increased in number to adult levels at 14 d and were significantly higher than in Snell dwarf (dw/dw) mice at 14 d (P < 0.05) and at subsequent ages (P < 0.01). In Snell dwarf mice, numbers of A12 neurons did not differ at 7, 14, and 21 d, decreased at 30 d (P < 0.05), and reached, at 60 d, 23% of the population in normal sibling mice (P < 0.01 compared with earlier ages). Neuron numbers in nonhypophysiotropic DA area A13 did not vary with age or phenotype. In A14, cell number was higher in both phenotypes at 14 d (P < 0.05 for DW/?; P < 0.01 for dw/dw); neuron number was lower in dw/dw than in DW/? mice at 30 d (P < 0.05) and 60 d (P < 0.01). Thus, compared with normal mice of the same strain, the A12 deficit is more severe in Snell (dw/dw) than in Ames (df/df) dwarf hypothalamus (48% of DF/?), as previously reported, and develops as a decline from the population present at 7 d rather than first increasing. A reduction in A14 neuron number also occurs in the Snell dwarf. Treatment of DW/dw- and dw/dw-containing litters with ovine PRL (50 μg/d, ip), beginning at 12 or 7 d and continuing until 42 d, resulted in TIDA neuron numbers in Snell dwarfs that were lower than those in normal siblings (P < 0.01 for both) but were higher than in untreated adult dwarfs and comparable to the TIDA population size in dwarfs at 7 d, indicating that PRL maintained this maximal number and prevented TIDA neuron dedifferentiation, which occurs in dwarf postnatal development.