tretinoin and Cardiovascular-Abnormalities

TAF4 (TATA-binding protein-associated factor 4) and its paralogue TAF4b are components of the TFIID core module. We inactivated the murine Taf4a gene to address Taf4 function during embryogenesis. Here we show that Taf4a(-/-) embryos survive until E9.5 where primary germ layers and many embryonic structures are identified showing Taf4 is dispensable for their specification. In contrast, Taf4 is required for correct patterning of the trunk and anterior structures, ventral morphogenesis and proper heart positioning. Overlapping expression of Taf4a and Taf4b during embryogenesis suggests their redundancy at early stages. In agreement with this, Taf4a(-/-) embryonic stem cells (ESCs) are viable and comprise Taf4b-containing TFIID. Nevertheless, Taf4a(-/-) ESCs do not complete differentiation into glutamatergic neurons and cardiomyocytes in vitro due to impaired preinitiation complex formation at the promoters of critical differentiation genes. We define an essential role of a core TFIID TAF in differentiation events during mammalian embryogenesis.

Topics: Animals; Biomarkers; Body Patterning; Cardiovascular Abnormalities; Cell Differentiation; Cell Survival; Embryo Loss; Embryonic Development; Female; Gene Expression Regulation, Developmental; Germ Cells; Mice; Mice, Inbred C57BL; Mouse Embryonic Stem Cells; Mutation; Myocardial Contraction; Myocytes, Cardiac; Neural Crest; Neurogenesis; Neurons; Phenotype; Pregnancy; Protein Subunits; Transcription Factor TFIID; Tretinoin

The cellular uptake of vitamin A from its RBP4-bound circulating form (holo-RBP4) is a homeostatic process that evidently depends on the multidomain membrane protein STRA6. In humans, mutations in STRA6 are associated with Matthew-Wood syndrome, manifested by multisystem developmental malformations. Here we addressed the metabolic basis of this inherited disease. STRA6-dependent transfer of retinol from RBP4 into cultured NIH 3T3 fibroblasts was enhanced by lecithin:retinol acyltransferase (LRAT). The retinol transfer was bidirectional, strongly suggesting that STRA6 acts as a retinol channel/transporter. Loss-of-function analysis in zebrafish embryos revealed that Stra6 deficiency caused vitamin A deprivation of the developing eyes. We provide evidence that, in the absence of Stra6, holo-Rbp4 provokes nonspecific vitamin A excess in several embryonic tissues, impairing retinoic acid receptor signaling and gene regulation. These fatal consequences of Stra6 deficiency, including craniofacial and cardiac defects and microphthalmia, were largely alleviated by reducing embryonic Rbp4 levels by morpholino oligonucleotide or pharmacological treatments.

Topics: Abnormalities, Multiple; Acyltransferases; Animals; Cardiovascular Abnormalities; Craniofacial Abnormalities; Disease Models, Animal; Eye; Gene Deletion; Gene Expression Regulation, Developmental; Homeostasis; Humans; Membrane Proteins; Membrane Transport Proteins; Mice; Morpholines; NIH 3T3 Cells; Oligonucleotides, Antisense; Retinol-Binding Proteins, Plasma; Syndrome; Time Factors; Transduction, Genetic; Tretinoin; Vitamin A; Zebrafish; Zebrafish Proteins

This review highlights the relevance of the neural crest (NC) as a developmental control mechanism involved in several pediatric surgical conditions and the investigative interest of following some of its known signaling pathways.. The participation of the NC in facial clefts, ear defects, branchial fistulae and cysts, heart outflow tract and aortic arch anomalies, pigmentary disorders, abnormal enteric innervation, neural tumors, hemangiomas, and vascular anomalies is briefly reviewed. Then, the literature on clinical and experimental esophageal atresia-tracheoesophageal fistula (EA-TEF) and congenital diaphragmatic hernia (CDH) is reviewed for the presence of associated NC defects. Finally, some of the molecular signaling pathways involved in both conditions (sonic hedgehog, Hox genes, and retinoids) are summarized.. The association of facial, cardiovascular, thymic, parathyroid, and C-cell defects together with anomalies of extrinsic and intrinsic esophageal innervation in babies and/or animals with both EA-TEF and CDH strongly supports the hypothesis that NC is involved in the pathogenesis of these malformative clusters. On the other hand, both EA-TEF and CDH are observed in mice mutant for genes involved in the previously mentioned signaling pathways.. The investigation of NC-related molecular pathogenic pathways involved in malformative associations like EA-TEF and CDH that are induced by chromosomal anomalies, chemical teratogens, and engineered mutations is a promising way of clarifying why and how some pediatric surgical conditions occur. Pediatric surgeons should be actively involved in these investigations.

Topics: Abnormalities, Multiple; Blood Vessels; Branchial Region; Cardiovascular Abnormalities; Cell Lineage; Cell Movement; Child; Child, Preschool; Enteric Nervous System; Esophageal Atresia; Face; Genes, Homeobox; Hedgehog Proteins; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Homeodomain Proteins; Humans; Infant; Infant, Newborn; Neoplasms; Neural Crest; Patched Receptors; Pigmentation Disorders; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Retinoic Acid; Signal Transduction; Smoothened Receptor; Syndrome; Transcription Factors; Tretinoin; Zinc Finger Protein GLI1