International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

G15 The Proximal Albino Deletions Identify Genes Essential for Anterior/Posterior Axis Specification and Development of Several Neuroendocrine Lineages of the Hypothalamus

Mary E. Wines1, Kristen Brown1, Jacques L. Michaud2, Charles De Rossi1, Stephen Wefer1, Lance Lee1, Tom Rosenquist1, Noah R. May3, Chen-Ming Fan3, and Bernadette C. Holdener1. 1Department of Biochemistry and Cell Biology and the Institute for Cell and Developmental Biology, State University of New York at Stony Brook, Stony Brook, NY 11794-5215; 2Service de Génétique Médicale, Hôpital Sainte-Justine, Montréal, Québec; 3Department of Embryology, Carnegie Institution of Washington, Baltimore, Maryland

We have constructed a BAC contig and transcript map spanning a 1.3 Mb region of mouse chromosome 7. The contig overlaps a chromosomal region removed by the more proximal albino deletions. Localization of deletion breakpoints within the contig defines the mesoderm development (mesd) critical region and identifies a new functional region required for development of several neuroendocrine lineages in the hypothalamus. Using radiation hybrid mapping we localized the syntenic region in humans to Chromosome 15 and have constructed a partial Human BAC contig. Curiously, a syndrome of severe mental retardation, spasticity, and tapetoretinal degeneration is overlaps this region.

Our continued phenotypic characterization of the deletions removing the mesoderm development (mesd) critical region supports the existence of distinct anterior and posterior organizing centers in early mammalian embryos. Furthermore, in situ hybridization and chimera analysis demonstrates that correct localization of the head organizer can occur independent of primitive streak function and that mesd is required in extra-embryonic tissue for trunk organizer function. We have identified two novel genes located within the 330-kb mesd functional region. Partial characterization of the 9-kb Mesd candidate-1 transcript has identified a 132 AA domain with similarity to the leucine rich region of the adenomatous polyposis coli (APC) protein. Similar domains are also observed in b-catenin, armadillo, and nuclear docking proteins. The mesd candidate 2 gene encodes a 188 AA protein related to a domain located in the central region of the talin protein. To determine which locus is responsible for the mesd defects and identify roles for these proteins throughout development, we are characterizing embryonic expression patterns, subcellular localization, and evaluating BAC transgenics.

A new functional region is defined by deletions encompassing the Aryl hydrocarbon receptor nuclear translocator-2 (Arnt2) gene. Arnt2 is a member of the bHLH-PAS family of transcriptional regulators and is homologous to Drosophila Tango. In Drosophila, Tango/Single-minded heterodimers are critical neural regulators. We find a similar role for the mouse Arnt2/Single-minded1 (SIM1) heterodimer. Through biochemical and phenotypic studies we demonstrate that Arnt2 and SIM1 form heterodimers, are expressed in overlapping regions of the hypothalamus, and are essential for development of several neuroendocrine lineages in the hypothalamus. These lineages are critical for output from the hypothalamus to the pituitary. In addition, high incidence of ventricular septal defects, major vessel patterning defects, and thymus hypoplasia are also associated with a deletion removing Arnt2 suggesting that Arnt2 may also play a critical role in neural crest migration, proliferation, and/or viability.


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