ABSTRACT
The proximal albino deletions identify several functional regions on mouse Chromosome 7 critical for differentiation of mesoderm (mesd), development of the hypothalamus neuroendocrine lineage (nelg), and function of the liver (hsdr1). Using comparative mapping and genomic sequence analysis, we have identified four novel genes and Il16 in the mesd deletion interval. Two of the novel genes, mesdc1 and mesdc2, are located within the mesd critical region defined by BAC transgenic rescue. We have investigated the fetal role of genes located outside the mesd critical region using BAC transgenic complementation of the mesd early embryonic lethality. Using human radiation hybrid mapping and BAC contig construction, we have identified a conserved region of human chromosome 15 homologous to the mesd, nelg, and hsdr1 functional regions. Three human diseases cosegregate with microsatellite markers used in construction of the human BAC/YAC physical map, including autosomal dominant nocturnal frontal lobe epilepsy (ENFL2; also known as ADNFLE), a syndrome of mental retardation, spasticity, and tapetoretinal degeneration (MRST); and a pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA).
Subject(s)
Chromosomes, Human, Pair 15/genetics , Genes , Mesoderm/physiology , Sequence Analysis, DNA , Abnormalities, Multiple/genetics , Animals , Chromosomes, Artificial, Bacterial , Contig Mapping , Epilepsy, Frontal Lobe/genetics , Expressed Sequence Tags , Genetic Linkage , Humans , Mice , Microsatellite Repeats , Molecular Sequence Data , Mutation , Phenotype , Physical Chromosome Mapping , Radiation Hybrid Mapping , Sequence Deletion , SyndromeABSTRACT
The cardiac neural crest (CNC) plays a central role in development of the thymus gland and cardiovascular system. Through morphological and histological characterization of embryos homozygous for the Del(7)Tyr(c-112K) and Del(7)Tyr(c-3H) albino deletions, we identified abnormalities that are consistent with aberrant development of tissues requiring CNC contributions. The defects include incompletely penetrant heart and great vessel patterning defects and hypoplastic thymus glands. The CNC phenotype is complemented by the partially overlapping deletion Del(7)Tyr(c-23DVT). Combined, these results suggest that a functional region necessary for development of CNC derived tissues is located between the Del(7)Tyr(c-23DVT) and Del(7)Tyr(c-112K) distal deletion breakpoints. This interval encompasses a functional region previously identified as important for juvenile survival (juvenile development and fertility, jdf). Using deletion mapping, we localized the Frizzled4 (Fzd4) gene to the jdf/thymus and cardiac development intervals.
Subject(s)
Gene Expression Regulation, Developmental , Heart/embryology , Heart/physiology , Proteins/genetics , Thymus Gland/embryology , Thymus Gland/physiology , Animals , Chromosome Mapping , Embryonic and Fetal Development/genetics , Frizzled Receptors , Mice , Mutation , Protein Biosynthesis , Receptors, Cell Surface , Receptors, G-Protein-CoupledABSTRACT
One major function of the hypothalamus is to maintain homeostasis by modulating the secretion of pituitary hormones. The paraventricular (PVN) and supraoptic (SON) nuclei are major integration centers for the output of the hypothalamus to the pituitary. The bHLH-PAS transcription factor SIM1 is crucial for the development of several neuroendocrine lineages within the PVN and SON. bHLH-PAS proteins require heterodimerization for their function. ARNT, ARNT2, and BMAL1 are the three known general heterodimerization partners for bHLH-PAS proteins. Here, we provide evidence that Sim1 and Arnt2 form dimers in vitro, that they are co-expressed in the PVN and SON, and that their loss of function affects the development of the same sets of neuroendocrine cell types within the PVN and SON. Together, these results implicate ARNT2 as the in vivo dimerization partner of SIM1 in controlling the development of these neuroendocrine lineages.
