No abstract

IntroductionThe steroid hormone 1␣,25-dihydroxyvitamin D 3 (1␣,25(OH) 2 D 3 ) is known for its important role in regulating calcium homeostasis and bone mineralization. 1 1␣,25(OH) 2 D 3 acts through a nuclear receptor, the vitamin D receptor (Vdr), which is a member of the steroid and thyroid hormone receptor superfamily. More recently, evidence has accumulated that the hormone can have important functions in the immune system. Expression of Vdr was found in different immune effector cells of the myeloid and lymphoid lineage under resting and activating conditions. 2,3 These findings contributed to the hypothesis that locally produced 1␣,25(OH) 2 D 3 may perform regulatory functions on those cells. Indeed, over the past few years it has been demonstrated that 1␣,25(OH) 2 D 3 can act as an important immunosuppressive modulator. 1␣,25(OH) 2 D 3 has been shown to suppress T-cell proliferation 4 and to decrease the production of the T helper type 1 (Th1) cytokines interleukin 2, interferon ␥ (IFN-␥), and tumor necrosis factor ␣ (TNF-␣), leading to the inhibition of Th1 cell development. 5 Besides its direct effects on T cells, 1␣,25(OH) 2 D 3 and its analogs are potent inhibitors of dendritic cell (DC) differentiation and maturation and can impair the capacity of DCs to induce alloreactive T-cell activation. 6,7 In line with this, Vdr-deficient mice have been shown to have an increased frequency of mature DCs in lymph nodes. 8 Additional support for the immunomodulatory role of 1␣,25(OH) 2 D 3 in vivo came from studies of autoimmune diseases in several different animal models. It has been demonstrated that 1␣,25(OH) 2 D 3 can prevent or suppress experimental autoimmune encephalomyelitis, 9 rheumatoid arthritis, 10 systemic lupus erythematosus, 11 type 1 diabetes, 12 and inflammatory bowel disease, 13,14 further supporting its potent suppressive effects on the immune system.In contrast to its well-characterized effects on adaptive immune responses, much less is known about the effects of 1␣,25(OH) 2 D 3 on effectors of innate immunity, especially on macrophages. It has been shown that 1␣,25(OH) 2 D 3 can induce the differentiation of myeloid progenitors into macrophages. 15,16 However, the effects of 1␣,25(OH) 2 D 3 on mature and activated macrophages that are involved in inflammatory reactions have not been characterized yet. Such possible effects might be of especial importance since it was demonstrated that macrophages can release biologically active 1␣,25(OH) 2 D 3 on activation with IFN-␥. 17,18 The production of 1␣,25(OH) 2 D 3 by activated macrophages is regulated by the IFN-␥-mediated induction of 1␣-hydroxylase expression, the enzyme controlling the last step of 1␣,25(OH) 2 D 3 synthesis. 17,18 In Supported by the National German Genome Network (NGFN; 01GR0439), EU FP5 project EUMORPHIIA (QLG2- CT-2002-00930), and Volkswagenstiftung.L.H. performed research and wrote the paper; J.B., J.E., and S.S. performed research; T.F. contributed reagents and analytical tools; R.G. and M.P.K analyzed data; R.B. initiate...

Mutations in the GLI3 gene have been identified in several human malformation syndromes. One of these autosomal dominant developmental disorders is Pallister-Hall syndrome (PHS; MIM146510), which is associated with central polydactyly and other malformations. Interestingly, the mutations in the GLI3 transcription factor gene identified in patients with PHS are restricted to the region 3' of the zinc finger-encoding domain, leaving this DNA-binding domain intact. We have investigated the consequences of this mutation on the development of multiple organ systems by introducing a targeted mutation in mice. We found that mice homozygous for the mutation showed a central polydactyly, thus modeling one of the major abnormalities of the human syndrome. Moreover, Gli3-mutant mice displayed a wide range of developmental abnormalities encompassing almost all of the common PHS features, including imperforate anus, gastrointestinal, epiglottis and larynx defects, abnormal kidney development, and absence of adrenal glands. Thus, our Gli3-mutant mice provide an excellent model for studies of both the pathogenesis of PHS and Gli3 functions in the development of the affected organ systems.

Background: Phagocytosis of apoptotic cells is fundamental to animal development, immune function and cellular homeostasis. The phosphatidylserine receptor (Ptdsr) on phagocytes has been implicated in the recognition and engulfment of apoptotic cells and in anti-inflammatory signaling. To determine the biological function of the phosphatidylserine receptor in vivo, we inactivated the Ptdsr gene in the mouse.

BackgroundCongenital heart defects are the leading non-infectious cause of death in children. Genetic studies in the mouse have been crucial to uncover new genes and signaling pathways associated with heart development and congenital heart disease. The identification of murine models of congenital cardiac malformations in high-throughput mutagenesis screens and in gene-targeted models is hindered by the opacity of the mouse embryo.ResultsWe developed and optimized a novel method for high-throughput multi-embryo magnetic resonance imaging (MRI). Using this approach we identified cardiac malformations in phosphatidylserine receptor (Ptdsr) deficient embryos. These included ventricular septal defects, double-outlet right ventricle, and hypoplasia of the pulmonary artery and thymus. These results indicate that Ptdsr plays a key role in cardiac development.ConclusionsOur novel multi-embryo MRI technique enables high-throughput identification of murine models for human congenital cardiopulmonary malformations at high spatial resolution. The technique can be easily adapted for mouse mutagenesis screens and, thus provides an important new tool for identifying new mouse models for human congenital heart diseases.