Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development. We demonstrate that mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families. Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5, a related and linked gene, cause anterior limb abnormalities in Holt-Oram syndrome. We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.
Zygotic genome activation (ZGA) is a nuclear reprogramming event that transforms the genome from transcriptional quiescence at fertilization to robust transcriptional activity shortly thereafter. The ensuing gene expression profile in the cleavage-stage embryo establishes totipotency and is required for further development. Although little is known about the molecular basis of ZGA, oocyte-derived mRNAs and proteins that alter chromatin structure are likely crucial. To test this hypothesis, we generated a maternal-effect mutation of Brg1, which encodes a catalytic subunit of SWI/SNF-related complexes, utilizing Cre-loxP gene targeting. In conditional-mutant females, BRG1-depleted oocytes completed meiosis and were fertilized. However, embryos conceived from BRG1-depleted eggs exhibited a ZGA phenotype including two-cell arrest and reduced transcription for ∼30% of expressed genes. Genes involved in transcription, RNA processing, and cell cycle regulation were particularly affected. The early embryonic arrest is not a consequence of a defective oocyte because depleting maternal BRG1 after oocyte development is complete by RNA interference (RNAi) also resulted in two-cell arrest. To our knowledge, Brg1 is the first gene required for ZGA in mammals. Depletion of maternal BRG1 did not affect global levels of histone acetylation, whereas dimethyl-H3K4 levels were reduced. These data provide a framework for understanding the mechanism of ZGA.[Keywords: Two-cell embryo; BRG1; SWI/SNF; maternal-effect mutation; transcriptional regulation; zygotic genome activation] Supplemental material is available at http://www.genesdev.org. In Drosophila and Xenopus, mRNAs stockpiled in the oocyte are stable after fertilization and regulate many aspects of embryonic development (Wolpert et al. 2002). Conversely, in mammals, oocyte-derived mRNAs are degraded shortly after fertilization and cannot direct more than the first few cell divisions . Therefore, zygotic genome activation (ZGA) must occur very early during mammalian development. In the mouse, a minor burst of ZGA toward the end of the one-cell stage is followed by a major burst during the two-cell stage (Latham et al. 1992;Vernet et al. 1992;Aoki et al. 1997;Thompson et al. 1998;Schultz 2002). In a variety of other mammals, including humans, the embryonic genome is activated in a similar stepwise manner at the four-to eight-cell stage or the eight-to 16-cell stage (Telford et al. 1990;Kanka 2003). ZGA is required for continued development because mRNAs common to the oocyte and embryo (e.g., genes involved in the maternal-to-zygotic transition and housekeeping genes) are replenished and many genes not transcribed in the oocyte are expressed for the first time. The outcome of ZGA is a novel gene expression profile that establishes the totipotent state of each blastomere in the cleavagestage embryo. This step is a prerequisite for future cell lineage commitments and differentiation events that underlie pattern formation and organogenesis.Changes in chromatin structure are thought ...
The Brg1 catalytic subunit of SWI/SNF-related complexes has been implicated in many developmental and physiological processes, but null homozygotes die as blastocysts prior to implantation. To circumvent this early embryonic lethality, we performed an ENU mutagenesis screen and generated a Brg1 hypomorph mutation in the ATPase domain. The mutant Brg1 protein is stable, assembles into SWI/SNF-related complexes, and exhibits normal ATPase activity but is unable to establish DNase I hypersensitivity sites characteristic of open chromatin. Mutant embryos develop normally until midgestation but then exhibit a distinct block in the development of the erythroid lineage, leading to anemia and death. The mutant Brg1 protein is recruited to the -globin locus, but chromatin remodeling and transcription are perturbed. Histone acetylation and DNA methylation are also affected. To our knowledge, Brg1 is the first chromatin-modifying factor shown to be required for -globin regulation and erythropoiesis in vivo. Not only does this mutation establish a role for Brg1 during organogenesis, it also demonstrates that ATPase activity can be uncoupled from chromatin remodeling.[Keywords: ATPase;  globin; Brg1; locus-control region; SWI/SNF; chromatin remodeling] Supplemental material is available at http://www.genesdev.org.
Holt-Oram syndrome is a developmental disorder affecting the heart and upper limb, the gene for which was mapped to chromosome 12 two years ago. We have now identified a gene for this disorder (HOS1). The gene (TBX5) is a member of the Brachyury (T) family corresponding to the mouse Tbx5 gene. We have identified six mutations, three in HOS families and three in sporadic HOS cases. Each of the mutations introduces a premature stop codon in the TBX5 gene product. Tissue in situ hybridization studies on human embryos from days 26 to 52 of gestation reveal expression of TBX5 in heart and limb, consistent with a role in human embryonic development.
Mammalian SWI/SNF-related complexes have been implicated in cancer based on some of the subunits physically interacting with retinoblastoma (RB) and other proteins involved in carcinogenesis. Additionally, several subunits are mutated or not expressed in tumor-derived cell lines. Strong evidence for a role in tumorigenesis in vivo, however, has been limited to SNF5 mutations that result primarily in malignant rhabdoid tumors (MRTs) in humans and MRTs as well as other sarcomas in mice. We previously generated a null mutation of the Brg1 catalytic subunit in the mouse and reported that homozygotes die during embryogenesis. Here, we demonstrate that Brg1 heterozygotes are susceptible to mammary tumors that are fundamentally different than Snf5 tumors. First, mammary tumors are carcinomas not sarcomas. Second, Brg1 þ /À tumors arise because of haploinsufficiency rather than loss of heterozygosity. Third, Brg1 þ /À tumors exhibit genomic instability but not polyploidy based on array comparative genomic hybridization results. We monitored Brg1 þ /À , Brm À/À double-mutant mice but did not observe any tumors resembling those from Snf5 mutants, indicating that the Brg1 þ /À and Snf5 þ /À tumor phenotypes do not differ simply because Brg1 has a closely related paralog whereas Snf5 does not. These findings demonstrate that BRG1 and SNF5 are not functionally equivalent but protect against cancer in different ways. We also demonstrate that Brg1 þ /À mammary tumors have relatively heterogeneous gene expression profiles with similarities and differences compared to other mouse models of breast cancer. The Brg1 þ /À expression profiles are not particularly similar to mammary tumors from Wap-T121 transgenic line where RB is perturbed. We were also unable to detect a genetic interaction between the Brg1 þ /À and Rb þ /À tumor phenotypes. These latter findings do not support a BRG1-RB interaction in vivo. IntroductionMuch work has focused on the role of mammalian SWI/ SNF-related complexes in cancer. SWI/SNF-related subunits physically interact with a number of proteins encoded by tumor-suppressor genes and proto-oncogenes (Muchardt and Yaniv, 2001;Roberts and Orkin, 2004). For example, BRM and BRG1 bind retinoblastoma (RB) and are required to repress the activity of E2F1, inhibit the transcription of cyclins A and E and mediate G 1 cell-cycle arrest in vitro. BRG1 and SNF5 can also act upstream of RB by activating the expression of several cyclin-dependent kinase inhibitors (p15 INK4b , p16 INK4A or p21 CIP1/WAF1 ), which leads to the inhibition of CDK2 and CDK4 and accumulation of the hypophosphorylated form of RB that mediates G 1 arrest.In addition to being associated with cancer-related proteins, the BRM, BRG1, SNF5, BAF155 and BAF250 subunits are mutated or not expressed in various tumor-derived cell lines (Muchardt and Yaniv, 2001). When tumor-derived cell lines are cultured, however, deletions and epigenetic alterations are selected for and accumulate. Because of this caveat, it is crucial to identify and characterize mu...
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