The gene apparently responsible for a heritable form of murine pituitary-dependent dwarfism (Ames dwarf, df) has been positionally cloned, identifying a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (Prop-1). The df phenotype results from an apparent failure of initial determination of the Pit-1 lineage required for production of growth hormone, prolactin or thyroid-stimulating hormone, resulting in dysmorphogenesis and failure to activate Pit-1 gene expression. These results imply that a cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineages in pituitary organogenesis.

The new mouse mutation little (lit) in the homozygous state causes a pituitary deficiency involving at least growth hormone (GH) and prolactin. The resultant growth failure of lit/lit mice was shown to be reversed by experimental conditions that enhanced levels of GH or GH and prolactin in the circulation. Two measures of growth, actual weight gain and bone dimension, were significantly improved by the physiological processes of pregnancy and pseudopregnancy, by extra-sellar graft of a normal mouse pituitary, and by treatment with GH but not prolactin. These data confirmed pituitary dysfunction as the basic defect caused by the mutation lit and showed that the GH deficiency is responsible for growth failure. However, the biological site of gene action, the pituitary or hypothalamus, has not been established. Little mice exhibit a number of characteristics similar to those of human genetic ateleotic dwarfism Type 1, namely genetic inheritance, time of onset of growth retardation, proportionate skeletal size reduction, and pituitary GH deficiency.

SummaryInterleukin 7 (IL-7) responsive B lineage precursors were greatly expanded in genetically hypogonadal female (HPG/Bm-kpg/kpg) mice that have a secondary deficiency in gonadal steroidogenesis.Estrogen replacement in these mice resulted in a dose-dependent reduction in B call precursors. More modest increases were documented in genetically normal mice that were surgically castrated. These findings complement other recent observations that B lymphopoiesis selectively declines in pregnant or estrogen-treated animals. Sex steroids have long been known to influence such disparate processes as bone physiology and tumor growth, in addition to their importance for reproductive function. We now show that these hormones are important negative regulators of B lymphopoiesis. Blood cell formation within bone marrow is thought to be controlled by close cellular interactions and the availability of cytokines that induce proliferation and differentiation of committed precursor cells. However, our understanding of this process is incomplete and especially so with respect to mechanisms that limit the production of particular blood cell types. We recently found that B lineage precursors, identified by their responsiveness to IL-7 and surface markers, were selectively depleted during normal pregnancy or after treatment with estrogens (1, 2). Since natural or artificial elevation of sex steroids suppresses B lymphopoiesis, it seemed possible that diminished endogenous levels of these hormones might result in expanded production of B lymphocytes.HPG/Bm-hFg/hpg (hpg) mice have a partial deletion of the hypothalamic gonadotropin releasing hormone (GNRH) gene and this results in a profound depression in synthesis of gonadotropins (follicle stimulating and lutdnizing hormones) (3-5). We now show that B lymphopoiesis is abnormally increased in these sex hormone-deficient animals and is normalized by estrogen replacement therapy. Materials and MethodsAnimals. Hypogonadal HPG/Bm-hpg/hpg (hpg) mice have a deletion in the GNRH gene, resulting in nonexistent gonadal sex steroid secretion and infantile reproductive tracts (3-5). The hFg mutation was maintained segregating within the HPG/Bm inbred strain and phenotypically normal (+/+ or hpg/+, hereafter termed +/?) animals were used as controls. Mutant hpg mice were identified by Southern blot analysis as described (6) and confirmed by measurement of uterine weights. Doubly homozygous hypogonadal severe combined immunodeficient (hpg/hpg scid/scid) mice were produced as previously described (6). Castrated mice were obtained from Charles River Laboratories (Wilmington, MA). 717Colony Assays. Bone marrow cells were prepared and suspended in 1 ml of assay medium as previously described (7). The semisolid agar doning assay for B lymphocyte precursors (CFU IL-7) was done with 10 ng recombinant mouse IL-7 (a gift from Immunex, Seattle WA). Mitogen responsive B cells were detected with 25 ~//ml of endotoxin (Difco, Detroit, MI) and the granulocyte/macrophage progenitor assay (CFU-G/M) was done w...

Circumstantial evidence has previously suggested gonad derived steroid hormones and melanogenesis related antigens may modify human alopecia areata (AA). AA-like hair loss can be induced in C3H/HeJ mice after skin allografts from spontaneous AA-affected mice. This inducible model was used to evaluate hormones and hair follicle melanocyte presence as disease-severity modifiers. Ten females and 9 males were gonadectomized and received AA-affected allografts. All gonadectomized mice had 2-4 weeks delay in AA onset relative to non-gonadectomized controls. Two females and 4 males failed to develop any AA by 25 weeks after grafting. The experiment was repeated with gonadectomized female and male mice plus non-gonadectomized mice subcutaneously implanted with silastic capsules containing 80 microg 17beta estradiol or 10 mg 5alpha dihydrotestosterone, respectively. Five of 11 ovariectomized and 9 of 11 non-ovariectomized, estradiol supplemented females developed AA with extremely rapid progression. Three of 8 castrated, but none of 11 non-castrated, dihydrotestosterone-supplemented males expressed AA. In a separate study, 14 mice were freeze-branded, producing white hair on the dorsal lumbar region, and later received full-thickness allografts. Thirteen mice developed patchy pigmented and non-pigmented hair loss. One mouse developed diffuse, pigmented hair loss, but with white hair survival persisting 25 weeks after grafting. The results suggest that gonadal steroid hormones can modulate C3H/HeJ mouse AA where estradiol promoted rapid progression of AA while dihydrotestosterone increased resistance to AA onset. In general, both pigmented and non-pigmented C3H/HeJ mouse hair is susceptible to AA. Murine AA susceptibility and severity clearly involves an interplay between genetic and epigenetic factors.

A predictably high incidence of true hermaphroditism (3%) among fetal BALB/cWt mice provided the opportunity for studying the cause of inherited hermaphroditism. G-banded liver metaphase chromosomes were analyzed from 20 fetal hermaphrodites and from 15 normal female and male littermate controls. All hermaphrodites and seven males were chromosomal mosaics, i.e. XO/XY or XO/XY/XYY. In each mosaic fetus there were more XO than XYY cells. From these findings we hypothesize that BALB/cWt hermaphrodites arise from non-disjunction and probable loss of the Y-chromosome during mitosis. Results from breeding experiments indicated that a defect in the BALB/cWt Y-chromosome per se accounts for its nondisjunction and loss.