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

A5 Function of Mouse Brahma Genes During Development

S. J. Bultman1, J. Mager1, F. Randazzo2, G. R. Crabtree 3, R. Krumlauf4, and T. R. Magnuson1. 1Department of Genetics, Case Western Reserve University, Cleveland, OH 44107; 2Chiron Corporation, Emeryville, CA 94608; 3Howard Hughes Medical Institute, Department of Developmental Biology, Stanford University, Stanford, CA 94305; 4National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK

Chromatin remodeling complexes utilize the energy of ATP hydrolysis to displace nucleosomes from promoter regions and enable genes to be transcribed. The yeast SWI/SNF complex was the first to be discovered and consists of 10 subunits with a total molecular weight of 2 MDa. SWI/SNF has been well conserved through evolution and has counterparts in Drosophila and mammals. The catalytic subunit in each species has DNA-dependent ATPase activity and is required for the complex to function. The gene encoding the catalytic subunit in Drosophila, brahma (brm), was first identified genetically as a member of the Trithorax group and is particularly important for maintainence of homeotic gene expression. Mammals have two genes, brahma (Brm) and brahma-related gene 1 (Brg1), encoding catalytic subunits that are 75% identical to each other at the amino-acid level. Brm was previously shown to be dispensable for embryonic development suggesting that a high degree of functional redundancy might exist between Brm and Brg1. We have generated a null mutation of Brg1 by gene targeting, and, surprisingly, homozygotes die during the peri-implantation stage. Moreover, blastocyst outgrowths demonstrate that neither the inner cell mass nor the trophectoderm survive in vitro. The dramatic difference in phenotypic severity might be due to the fact that Brg1 is expressed at higher levels than Brm in the pre-implantation embryo. The objective of current double-knockout and immunofluorescence experiments is to determine whether Brg1 homozygotes survive beyond the 2- to 4-cell stage to the peri-implantation stage because of compensation from Brm or maternal loading of wild-type Brg1 protein. If either is the case, Brg1 might play a role in activation of the zygotic genome. In addition , in order to elucidate the function of Brg1 later during post-implantation development, an allelic series is being generated. As a first step, transgenic embryos have been generated which express a dominant-negative Brg1 protein defective in ATP binding, and preliminary analyses suggest they are developmentally delayed and exhibit neural tube defects at embryonic day (E) 9.5.

 


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