Alpha-fetoprotein controls female fertility and prenatal development of the gonadotropin-releasing hormone pathway through an antiestrogenic action

It has been shown previously that female mice homozygous for an alpha-fetoprotein (AFP) null allele are sterile as a result of anovulation, probably due to a defect in the hypothalamic-pituitary axis. Here we show that these female mice exhibit specific anomalies in the expression of numerous genes in the pituitary, including genes involved in the gonadotropin-releasing hormone pathway, which are underexpressed. In the hypothalamus, the gonadotropin-releasing hormone gene, Gnrh1, was also found to be down-regulated. However, pituitary gene expression could be normalized and fertility could be rescued by blocking prenatal estrogen synthesis using an aromatase inhibitor. These results show that AFP protects the developing female brain from the adverse effects of prenatal estrogen exposure and clarify a long-running debate on the role of this fetal protein in brain sexual differentiation.

The effect of prenatal or early postnatal irradiation on the production of anti-arsonate antibodies and Cross-reactive idiotypes

Preliminary studies on the long-term effects of prenatal and early postnatal irradiation on the immune response to arsonate were performed using A/J mice. Pregnant mice were irradiated (0·5 Gy, X-rays) or sham-irradiated on a single occasion during gestation (between day 5 and 18 post-conception). Alternatively, newborn mice received the same treatment between day 2 and 7 after birth. Mice were immunized with keyhole limpet haemocyanin-arsonate (KLH-Ars) in adjuvant from 2 months after birth. The levels of specific antibodies to arsonate (anti-Ars) were measured by radioimmunoassay. In addition, the Ars-related cross-reactive idiotype (CRIA) was measured by the haemagglutination technique. In the primary response the titre of anti-Ars was reduced in animals that had been irradiated between day 12 and 15 of gestation. In the second response, in contrast, they had increased levels of anti-Ars. After immunization with KLH-Ars, high levels of CRIA were observed in all groups. However, in mice irradiated 18-20 days after conception the level of CRIA was often much higher than the level of anti-Ars, indicating that a large proportion of the CRIA-positive molecules were not specific for Ars. Thus, in this particular case, some specificity of the immune response was lost after irradiation. The expression of recurrent idiotypes may be a sensitive indicator of immunological perturbations after irradiation. © 1988 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception

PR homology domain-containing member 12 (PRDM12) is a highly evolutionary conserved member of the Prdm family of transcription factors that play essential roles in many cell fate decisions. In human, PRDM12 coding mutations have been recently identified in several patients with hereditary sensory and autonomic neuropathy (HSAN) (submitted elsewhere). Here we show that PRDM12 is involved in sensory neurogenesis in Xenopus and that several of the human Prdm12 mutants show altered structure, subcellular localization and function. In Drosophila, we demonstrate that the sensory neuron specific RNAi knockdown of the Prdm12 ortholog Hamlet induces impaired nociception and that a similar phenotype is observed in hypomorph hamlet mutants. In human fibroblasts of patients with PRDM12 mutations, we identified additional possible downstream target genes including thyrotropin-releasing hormone degrading enzyme (TRHDE). Knock-down of fly TRHDE in sensory neurons resulted in altered nociceptive neurons and impaired nociception. Collectively, these findings provide the first evidence showing that Prdm12 plays an important role in sensory neuron development. They also suggest that it has a critical evolutionarily conserved role in pain perception via modulation of the TRH signaling pathway.

Human dendritic cell maturation and cytokine secretion upon stimulation with Bordetella pertussis filamentous haemagglutinin.

In addition to antibodies, Th1-type T cell responses are also important for long-lasting protection against pertussis. However, upon immunization with the current acellular vaccines, many children fail to induce Th1-type responses, potentially due to immunomodulatory effects of some vaccine antigens, such as filamentous haemagglutinin (FHA). We therefore analysed the ability of FHA to modulate immune functions of human monocyte-derived dendritic cells (MDDC). FHA was purified from pertussis toxin (PTX)-deficient or from PTX- and adenylate cyclase-deficient Bordetella pertussis strains, and residual endotoxin was neutralized with polymyxin B. FHA from both strains induced phenotypic maturation of human MDDC and cytokine secretion (IL-10, IL-12p40, IL-12p70, IL-23 and IL-6). To identify the FHA domains responsible for MDDC immunomodulation, MDDC were stimulated with FHA containing a Gly→Ala substitution at its RGD site (FHA-RAD) or with an 80-kDa N-terminal moiety of FHA (Fha44), containing its heparin-binding site. Whereas FHA-RAD induced maturation and cytokine production comparable to those of FHA, Fha44 did not induce IL-10 production, but maturated MDDC at least partially. Nevertheless, Fha44 induced the secretion of IL-12p40, IL-12p70, IL-23 and IL-6 by MDDC, albeit at lower levels than FHA. Thus, FHA can modulate MDDC responses in multiple ways, and IL-10 induction can be dissociated from the induction of other cytokines.

Stimulation of apolipoprotein D secretion by steroids coincides with inhibition of cell proliferation in human LNCaP prostate cancer cells

Although steroid hormones are known to play a predominant role in the regulation of cell growth in hormone-sensitive cancers, their mechanisms of action, especially their interaction with growth factors and/or growth inhibitors, is poorly understood. We have recently observed that the effects of androgens and estrogens on the expression of the major protein found in human breast gross cystic disease fluid, protein-24, are opposite to their respective action on cell proliferation in human breast cancer cell lines. Somewhat surprisingly, the recent elucidation of the amino acid sequence of this progesterone binding protein reveals that this tumor marker is apolipoprotein D (apo D), a member of a superfamily of lipophilic ligand carrier proteins. The present study was designed to determine whether apo D is secreted by human prostate cancer cells and could thus be a new marker of steroid action in these cancer cells, and whether the sex steroid-induced stimulation of apo D secretion coincides with inhibition of cell proliferation. We took advantage of the biphasic pattern of the effect of steroids on the proliferation of the human prostate cancer LNCaP cell line, which offers the opportunity to discriminate between positive and negative steroid receptor-regulated cell growth processes. A 10-day exposure to low concentrations of dihydrotestosterone and testosterone caused a potent stimulation of LNCaP cell proliferation, whereas incubation with higher concentrations of these androgens led to a progressive decrease in cell proliferation towards basal levels. The biphasic action of androgens was also observed on apo D secretion, the effects on apo D secretion being inversely related to their action on LNCaP cell proliferation. Similar opposite biphasic effects were also observed with 9 other steroids, thus indicating that the stimulation of secretion of this new biochemical marker coincides with inhibition of cell proliferation in LNCaP human prostatic cancer cells.