The winged helix gene,Foxb1, controls development of mammary glands and regions of the CNS that regulate the milk-ejection reflex

Kloetzli, Jacqueline M.; Fontaine-Glover, Iris A.; Brown, Erin R.; Kuo, Myrna; Labosky, Patricia A.

doi:10.1002/1526-968x(200102)29:2<60::aid-gene1006>3.0.co;2-l

Cited by 17 publications

(12 citation statements)

References 46 publications

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“…However, we found no differences in Foxb1 expression, suggesting that Foxb1 does not mediate the Dmbx1 mutant phenotype. It was proposed that morphological defects in the inferior colliculi were responsible for the lactation defect of Foxb1 mutant mice (12). This proposal suggests a similar cause for the Dmbx1 maternal phenotypes, since an aberrant expression of Dmbx1-lacZ was observed in the inferior colliculus in Dmbx1 mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Neonatal Lethality, Dwarfism, and Abnormal Brain Development in Dmbx1 Mutant Mice

Ohtoshi

Behringer

2004

Molecular and Cellular Biology

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Dmbx1 encodes a paired-like homeodomain protein that is expressed in developing neural tissues during mouse embryogenesis. To elucidate the in vivo role of Dmbx1, we generated two Dmbx1 mutant alleles. Dmbx1 ؊ lacks the homeobox and Dmbx1 z is an insertion of a lacZ reporter gene. Dmbx1 z appears to be a faithful reporter of Dmbx1 expression during embryogenesis and after birth. Dmbx1-lacZ expression was detected in the superior colliculus, cerebellar nuclei, and subpopulations of the medulla oblongata and spinal cord. Some Dmbx1 homozygous mutant mice died during the neonatal period, while others survived to adulthood; however, their growth was impaired. Both heterozygous and homozygous mutant offspring from Dmbx1 homozygous mutant females exhibited a low survival rate and poor growth. However, even wild-type pups fostered onto Dmbx1 homozygous mutant females grew poorly, suggesting a Dmbx1-dependent nursing defect. Dmbx1 mutant mice had an aberrant Dmbx1-lacZ expression pattern in the nervous system, indicating that they had abnormal brain development. These results demonstrate that Dmbx1 is required for postnatal survival, growth, and brain development.The central nervous system (CNS) is derived from the neural plate, a tissue that arises from the anterior epiblast of the mouse gastrula (28). Complex morphogenetic processes transform the relatively flat neural plate into the neural tube. By the time the neural tube is formed, it has differentiated morphological segments along the anterior-posterior axis and is divided into several compartments called neuromeres. The neuromeres in the forebrain and hindbrain comprise six prosomeres and eight rhombomeres, respectively. This segmentation is induced and maintained by the expression of segment-specific genes, including homeobox genes that encode homeodomain-containing transcription factors.The homeodomain is a conserved DNA-binding motif that consists of ϳ60 amino acid residues. The homeoproteins are divided into two groups, clustered and dispersed, according to how they are distributed on the chromosomes. Mammals have four Hox gene clusters. Homeobox genes belonging to the dispersed class are further divided into several subclasses, primarily by the homeodomain sequences.There are many homeobox genes that are known to be expressed in developing brains and/or mature nervous systems in mice (32). Several Hox genes are expressed in specific rhombomeres and are required for the identification of neuromeres. In the forebrain, several dispersed-class homeobox genes that belong to Dlx, Emx, Nkx, and paired-like subclasses are expressed in region-specific patterns. Based on the restricted expression pattern of regulatory genes and morphological observations, a prosomeric model of forebrain patterning was proposed (27). The embryonic midbrain is a compartment structure located between the forebrain and hindbrain and can be considered one of the neuromeres. Otx genes are expressed in the embryonic midbrain and mark the midbrain-hindbrain boundary.To date, Ͼ30 paired-like h...

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Section: Discussionmentioning

confidence: 99%

Neonatal Lethality, Dwarfism, and Abnormal Brain Development in Dmbx1 Mutant Mice

Ohtoshi

Behringer

2004

Molecular and Cellular Biology

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“…Interestingly, Hoxa7, Foxb1, Gata3 and Runx1 are expressed or required during normal development of the mammary gland. [39][40][41][42] Hypermethylation of Hoxa7 and Sox17 has been observed in several human cancers, including breast cancer. [43][44][45][46][47][48] Moreover, downregulation of Dmrt2 and upregulation of Gata3 and Runx1 in human breast carcinoma has been reported.…”

Section: Cancer Genetics and Epigeneticsmentioning

confidence: 99%

Epigenetic dysregulation of key developmental genes in radiation‐induced rat mammary carcinomas

Daino

Nishimura

Imaoka

et al. 2018

Intl Journal of Cancer

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With the increase in the number of long-term cancer survivors worldwide, there is a growing concern about the risk of secondary cancers induced by radiotherapy. Epigenetic modifications of genes associated with carcinogenesis are attractive targets for the prevention of cancer owing to their reversible nature. To identify genes with possible changes in functionally relevant DNA methylation patterns in mammary carcinomas induced by radiation exposure, we performed microarray-based global DNA methylation and expression profiling in γ-ray-induced rat mammary carcinomas and normal mammary glands. The gene expression profiling identified dysregulation of developmentally related genes, including the downstream targets of polycomb repressive complex 2 (PRC2) and overexpression of enhancer of zeste homolog 2, a component of PRC2, in the carcinomas. By integrating expression and DNA methylation profiles, we identified ten hypermethylated and three hypomethylated genes that possibly act as tumor-suppressor genes and oncogenes dysregulated by aberrant DNA methylation; half of these genes encode developmental transcription factors. Bisulfite sequencing and quantitative PCR confirmed the dysregulation of the polycomb-regulated developmentally related transcription-factor genes Dmrt2, Hoxa7, Foxb1, Sox17, Lhx8, Gata3 and Runx1. Silencing of Hoxa7 was further verified by immunohistochemistry. These results suggest that, in radiation-induced mammary gland carcinomas, PRC2-mediated aberrant DNA methylation leads to dysregulation of developmentally related transcription-factor genes. Our findings provide clues to molecular mechanisms linking epigenetic regulation and radiation-induced breast carcinogenesis and underscore the potential of such epigenetic mechanisms as targets for cancer prevention.

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“…Other Fox genes have also been shown to regulate diverse aspects of neural development. BF-1 (Foxg1) is required for normal proliferation and differentiation of telencephalic neuroepithelial cells, whereas a significant percentage of Fkh5 Ϫ/Ϫ (Foxb1 Ϫ/Ϫ ) embryos display an open neural tube and female Fkh5 Ϫ/Ϫ mice that survive and reproduce have specific neural defects in the milk ejection reflex (19,38).…”

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confidence: 99%

Transcriptional and DNA Binding Activity of the Foxp1/2/4 Family Is Modulated by Heterotypic and Homotypic Protein Interactions

Weidenfeld

Morrisey

2004

Molecular and Cellular Biology

286

340

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Foxp1, Foxp2, and Foxp4 are large multidomain transcriptional regulators belonging to the family of winged-helix DNA binding proteins known as the Fox family. Foxp1 and Foxp2 have been shown to act as transcriptional repressors, while regulatory activity of the recently identified Foxp4 has not been determined. Given the importance of this Fox gene subfamily in neural and lung development, we sought to elucidate the mechanisms by which Foxp1, Foxp2, and Foxp4 repress gene transcription. We show that like Foxp1 and Foxp2, Foxp4 represses transcription. Analysis of the N-terminal repression domain in Foxp1, Foxp2, and Foxp4 shows that this region contains two separate and distinct repression subdomains that are highly homologous termed subdomain 1 and subdomain 2. However, subdomain 2 is not functional in Foxp4. Screening for proteins that interact with subdomains 1 and 2 of Foxp2 using yeast two-hybrid analysis revealed that subdomain 2 binds to C-terminal binding protein 1, which can synergistically repress transcription with Foxp1 and Foxp2, but not Foxp4. Subdomain 1 contains a highly conserved leucine zipper similar to that found in N-myc and confers homo-and heterodimerization to the Foxp1/2/4 family members. These interactions are dependent on the conserved leucine zipper motif. Finally, we show that the integrity of this subdomain is essential for DNA binding, making Foxp1, Foxp2, and Foxp4 the first Fox proteins that require dimerization for DNA binding. These data reveal a complex regulatory mechanism underlying Foxp1, Foxp2, and Foxp4 activity, demonstrating that Foxp1, Foxp2, and Foxp4 are the first Fox proteins reported whose activity is regulated by homo-and heterodimerization.

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The winged helix gene,Foxb1, controls development of mammary glands and regions of the CNS that regulate the milk-ejection reflex

Cited by 17 publications

References 46 publications

Neonatal Lethality, Dwarfism, and Abnormal Brain Development in Dmbx1 Mutant Mice

Neonatal Lethality, Dwarfism, and Abnormal Brain Development in Dmbx1 Mutant Mice

Epigenetic dysregulation of key developmental genes in radiation‐induced rat mammary carcinomas

Transcriptional and DNA Binding Activity of the Foxp1/2/4 Family Is Modulated by Heterotypic and Homotypic Protein Interactions

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