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The molecular mechanisms that underlie spleen development and congenital asplenia, a condition linked to increased risk of overwhelming infections, remain largely unknown. The transcription factor TLX1 controls cell fate specification and organ expansion during spleen development, and Tlx1 deletion causes asplenia in mice. Deregulation of TLX1 expression has recently been proposed in the pathogenesis of congenital asplenia in patients carrying mutations of the gene-encoding transcription factor SF-1. Herein, we have shown that TLX1-dependent regulation of retinoic acid (RA) metabolism is critical for spleen organogenesis. In a murine model, loss of Tlx1 during formation of the splenic anlage increased RA signaling by regulating several genes involved in RA metabolism. Uncontrolled RA activity resulted in premature differentiation of mesenchymal cells and reduced vasculogenesis of the splenic primordium. Pharmacological inhibition of RA signaling in Tlx1- deficient animals partially rescued the spleen defect. Finally, spleen growth was impaired in mice lacking either cytochrome P450 26B1 (Cyp26b1), which results in excess RA, or retinol dehydrogenase 10 (Rdh10), which results in RA deficiency. Together, these findings establish TLX1 as a critical regulator of RA metabolism and provide mechanistic insights into the molecular determinants of human congenital asplenia., Introduction The mammalian spleen is a secondary lymphoid organ that plays a central role in host defense. As a result, asplenia or hyposplenia and postsplenectomy patients often have an increased [...]

The developmental abnormalities associated with disruption of signaling by retinoic acid (RA), the biologically active form of vitamin A, have been known for decades from studies in animal models and humans. These include defects in the respiratory system, such as lung hypoplasia and agenesis. However, the molecular events controlled by RA that lead to formation of the lung primordium from the primitive foregut remain unclear. Here, we present evidence that endogenous RA acts as a major regulatory signal integrating Wnt and Tgfβ pathways in the control of Fgf10 expression during induction of the mouse primordial lung. We demonstrated that activation of Wnt signaling required for lung formation was dependent on local repression of its antagonist, Dickkopf homolog 1 (Dkkl), by endogenous RA. Moreover, we showed that simultaneously activating Wnt and repressing Tgfβ allowed induction of both lung buds in RA-deficient foreguts. The data in this study suggest that disruption of Wnt/Tgf β/Fgf10 interactions represents the molecular basis for the classically reported failure to form lung buds in vitamin A deficiency., Introduction Congenital abnormalities of the respiratory system are often part of multiorgan syndromes associated with genetic, environmental, or nutritional imbalances. The lungs and trachea, as well as the thyroid, stomach, [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2006.05.019 Byline: Zengxin Wang (a), Pascal Dolle (b), Wellington V. Cardoso (c), Karen Niederreither (a) Keywords: Retinoids; Lung; Stomach; Liver; Fgf10; Sonic hedgehog; Hox genes; Tbx genes Abstract: Retinoic acid (RA) is an embryonic signaling molecule regulating a wide array of target genes, thereby being a master regulator of patterning and differentiation in a variety of organs. Here we show that mouse embryos deficient for the RA-synthesizing enzyme retinaldehyde dehydrogenase 2 (RALDH2), if rescued from early lethality by maternal RA supplementation between E7.5 and E8.5, lack active RA signaling in the foregut region. The resulting mutants completely fail to develop lungs. Development of more posterior foregut derivatives (stomach and duodenum), as well as liver growth, is also severely affected. A primary lung bud is specified in the RA-deficient embryos, which fails to outgrow due to defective FGF10 signaling and lack of activation of FGF-target genes, such as Pea3 and Bmp4 in the epithelium. Specific Hox and Tbx genes may mediate these RA regulatory effects. Development of foregut derivatives can be partly restored in mutants by extending the RA supplementation until at least E10.5, but lung growth and branching remain defective and a hypoplastic lung develops on the right side only. Such conditions poorly restore FGF10 signaling in the lung buds. Explant culture of RALDH2-deficient foreguts show a capacity to undergo lung budding and early branching in the presence of RA or FGF10. Our data implicate RA as a regulator of gene expression in the early embryonic lung and stomach region upstream of Hox, Tbx and FGF10 signaling. Author Affiliation: (a) Departments of Medicine and Molecular and Cellular Biology, Center for Cardiovascular Development, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA (b) Institut de Genetique et de Biologie Moleculaire et Cellulaire, UMR 7104 du CNRS, U. 596 de l'INSERM, Universite Louis Pasteur, BP 10142, 67404 Illkirch Cedex, CU de Strasbourg, France (c) Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA Article History: Received 21 February 2006; Revised 24 April 2006; Accepted 15 May 2006

Biochemical process which will regulate morphogenesis and patterning in mammals is examined.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2005.12.017 Byline: Arthur C.-K. Chung (a), Xueping Xu (a), Karen A. Niederreither (a)(b), Austin J. Cooney (a) Keywords: Nuclear receptor; GCNF; Isthmic organizer; Midbrain-hindbrain boundary Abstract: The isthmic organizer, which is located at the midbrain-hindbrain boundary, is important for midbrain development. The mechanism by which the development of the organizer is initiated and maintained is not well understood. Inactivation of the gene encoding the orphan nuclear receptor, GCNF, diminishes the expression of secreted signaling molecules, Fgf8 and Wnt1, the paired box genes Pax2/5, En1/2, and homeodomain transcription factor Gbx2; all of which are essential for isthmic organizer function. In addition, full neuronal differentiation is not observed in the midbrain region of GCNF.sup.-/- embryos. Increased cell death may contribute to the loss of midbrain structure in GCNF.sup.-/- embryos. These results indicate that GCNF is required for establishment of the isthmic organizer, thereby regulating the midbrain development. Author Affiliation: (a) Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA (b) Department of Medicine, Center for Cardiovascular Development, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA Article History: Received 28 June 2005; Revised 17 November 2005; Accepted 6 December 2005

Using a study on mice, the influence of signaling activity of retinoic acid receptors on initial lung development is examined.

During embryogenesis, the pancreas arises from dorsal and ventral pancreatic protrusions from the primitive gut endoderm upon induction by different stimuli from neighboring mesodermal tissues. Recent studies have shown that Retinoic Acid (RA) signaling is essential for the development of the pancreas in non-mammalian vertebrates. To investigate whether RA regulates mouse pancreas development, we have studied the phenotype of mice with a targeted deletion in the retinaldehyde dehydrogenase 2 (Raldh2) gene, encoding the enzyme required to synthesize RA in the embryo. We show that Raldh2 is expressed in the dorsal pancreatic mesenchyme at the early stage of pancreas specification. RA-responding cells have been detected in pancreatic endodermal and mesenchymal cells. Raldh2-deficient mice do not develop a dorsal pancreatic bud. Mutant embryos lack Pdx1 expression, an essential regulator of early pancreas development, in the dorsal but not the ventral endoderm. In contrast to Pdx1-deficient mice, the early glucagon-expressing cells do not develop in Raldh2 knockout embryos. Shh expression is, as in the wild-type embryo, excluded from the dorsal endodermal region at the site where the dorsal bud is expected to form, indicating that the dorsal bud defect is not related to a mis-expression of Shh. Mesenchymal expression of the LIM homeodolnain protein Is11, required for the formation of the dorsal mesenchyme, is altered in Raldh2-/- embryos. The homeobox gene Hlxb9, which is essential for the initiation of the pancreatic program in the dorsal foregut endoderm, is still expressed in Raldh2-/- dorsal epithelium but the number of HB9-expressing cells is severely reduced. Maternal supplementation of RA rescues early dorsal pancreas development and restores endodermal Pdx1 and mesenchymal Is11 expression as well as endocrine cell differentiation. These findings suggest that RA signaling is important for the proper differentiation of the dorsal mesenchyme and development of the dorsal endoderm. We conclude that RA synthesized in the mesenchyme is specifically required for the normal development of the dorsal pancreatic endoderm at a stage preceding Pdx1 function. Keywords: Pancreas; Raldh2; Retinoids; Foregut; Endoderm; Mesenchymc; Shh; Is11; H1xb9

Tbx20 is a member of the T-box transcription factor family expressed in the forming hearts of vertebrate and invertebrate embryos. We report here analysis of Tbx20 expression during murine cardiac development and assessment of DNA-binding and transcriptional properties of Tbx20 isoforms. Tbx20 was expressed in myocardium and endocardium, including high levels in endocardial cushions, cDNAs generated by alternative splicing encode at least four Tbx20 isoforms, and Tbx20a uniquely carried strong transactivation and transrepression domains in its C terminus. Isoforms with an intact T-box bound specifically to DNA sites resembling the consensus brachyury half site, although with less avidity compared with the related factor, Tbx5. Tbx20 physically interacted with cardiac transcription factors Nkx2-5, GATA4, and GATA5, collaborating to synergistically activate cardiac gene expression. Among cardiac GATA factors, there was preferential synergy with GATA5, implicated in endocardial differentiation. In Xenopus embryos, enforced expression of Tbx20a, but not Tbx20b, led to induction of mesodermal and endodermal lineage markers as well as cell migration, indicating that the long Tbx20a isoform uniquely bears functional domains that can alter gene expression and developmental behaviour in an in vivo context. We propose that Tbx20 plays an integrated role in the ancient myogenic program of the heart, and has been additionally coopted during evolution of vertebrates for endocardial cushion development. Keywords: T-box; Tbx20; Tbx5; Tbx genes; Nkx2-5; GATA; Heart development; Embryonic development; Transcription factor; Xenopus; Cell migration

This study reports a morphological, skeletal, and molecular characterization of the supernumerary limbs induced by systemic administration of all-trans retinoic acid to egg-cylinder stage mouse embryos. As initially described by Rutledge et al. (Proc. Natl. Acad. Sci. USA 91, 5436, 1994), we have found that oral administration of all-trans retinoic acid (70 mg/kg body weight) at 5.5 days postcoitum induced the formation of supernumerary limbs. Most often, these arose as a pair of extra buds located caudally and ventrally to the normal (orthotopic) hindlimb buds without duplication of the lower body axis. The resulting one or two supernumerary hindlimbs were connected to an imperfectly mirror-image-duplicated pelvic girdle. Variable truncations of the stylopodium and zeugopodium skeleton, as well as abnormal splitting of the distal skeleton, were frequently observed. The apical ectodermal ridge of the extra limb buds expressed expected growth factor genes. However, an ectopic anterior expression of Sonic hedgehog and Hoxd-13 was seen in the supernumerary buds, suggesting that these buds would incorporate potential polarizing cells of the hindlimb or genital field and generate an ectopic polarizing zone. This is consistent with the reverse orientation of most supernumerary limbs at later stages. Some of the buds did not express limb-specific markers and were thus expected to degenerate or form nonlimb structures, as observed in an adult specimen. Less frequently, extra limb buds with normal polarity were associated to a duplicated lower body axis. Retinoic acid also generated a novel type of duplication in which 'twin' hindlimbs with two parallel apical ectodermal ridges and zones of polarizing activity arose on one side of the embryo.

The ability of the pro-alpha2(I) collagen gene promoter to direct tissue-specific expression was further characterized in studies with transgenic mice. The study used the beta-galactosidase reporter gene to localize transgene expression during embryogenesis. The results showed that 350 base pairs of promoter sequence linked to beta-galactosidase was enough to confer tissue and cell specificity. It was proposed that transforminggrowth factor-beta-1 and cell-specific transcription factors control the the tissue specific expression of pro-alpha2(I) collagene gene during embryogenesis.