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Identification and characterization of Rhox13, a novel X-linked mouse homeobox gene.

ABSTRACT: Homeobox genes encode transcription factors whose expression organizes programs of development. A number of homeobox genes expressed in reproductive tissues have been identified recently, including a colinear cluster on the X chromosome in mice. This has led to an increased interest in understanding the role(s) of homeobox genes in regulating development of reproductive tissues including the testis, ovary, and placenta. Here we report the identification and characterization of a novel homeobox gene of the paired-like class on the X chromosome distal to the reproductive homeobox (Rhox) cluster in mice. Transcripts are found in the testis and ovary as early as 13.5 days post coitum (dpc). Transcription ceases in the ovary by 3 days post partum (dpp), but continues in the testis through adulthood. The Rhox13 gene encodes a 25.3 kDa protein expressed in the adult testis in germ cells at the basal aspect of the seminiferous epithelium.

SUBMITTER: Geyer CB

PROVIDER: S-EPMC2614869 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Identification and characterization of Rhox13, a novel X-linked mouse homeobox gene.

Geyer Christopher B CB Eddy Edward M EM

Gene 20080715 2

Homeobox genes encode transcription factors whose expression organizes programs of development. A number of homeobox genes expressed in reproductive tissues have been identified recently, including a colinear cluster on the X chromosome in mice. This has led to an increased interest in understanding the role(s) of homeobox genes in regulating development of reproductive tissues including the testis, ovary, and placenta. Here we report the identification and characterization of a novel homeobox g ...[more]

PMID: 18675325

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Project description:Hepatocellular carcinoma (HCC) is sexually disparate in humans, with a significantly increased prevalence in males. The molecular mechanisms by which the inhibition or development of liver cancer are facilitated require further investigation with regard to sex factors affecting disease progression. In the present study, functional signatures of differentially expressed genes (DEGs) were screened in female and male tumors via bioinformatics analysis. The following gene chip expression profiles were downloaded from the Gene Expression Omnibus: GSE19665, GSE23342 and GSE9843. They comprised cancerous and non‑cancerous tissue from patients with HCC and included critical sex features. Further evaluation of selected DEGs in the two sexual groups was performed via hierarchical clustering analysis. Venn diagram and functional protein‑protein interaction (PPI) network analyses were performed. Survival analysis of patients with differences in gene expression levels was subsequently performed using the Kaplan‑Meier Plotter database. Certain identified DEGs were common in female and male tumor samples, whereas others exhibited a sexually‑biased expression profile. Gene Ontology revealed that the cell cycle module 'biological process' was enriched in tumors derived from both sexes, whereas the metabolic pathways and drug metabolism modules were only significantly enriched in cancer tissues from male subjects. A number of hub DEGs in the cell cycle and p53 signaling pathways were involved in significant protein‑protein interaction (PPI) modules, including CDK1 and CCNB1. These DEGs were upregulated in tumors derived from female subjects compared with those derived from male subjects, and could be used as markers of poor prognosis in male patients. Other genes, such as CYP3A4 and SERPINA4, were identified in metabolic pathways, and were downregulated in male compared with female subjects. These genes were associated with a decreased survival rate. The data demonstrated that sex differences in physiology may regulate the levels of gene expression and/or activity, including gene function associated with oncogenesis and the outcomes of liver cancer. Additional surveys are required to explore in detail the molecular mechanisms underlying the differences in gene expression between the two sexes during the development of liver cancer.

Project description:BackgroundThe Six1 homeobox gene is highly expressed in the embryonic mammary gland, continues to be expressed in early postnatal mammary development, but is lost when the mammary gland differentiates during pregnancy. However, Six1 is re-expressed in breast cancers, suggesting that its re-instatement in the adult mammary gland may contribute to breast tumorigenesis via initiating a developmental process out of context. Indeed, recent studies demonstrate that Six1 overexpression in the adult mouse mammary gland is sufficient for initiating invasive carcinomas, and that its overexpression in xenograft models of mammary cancer leads to metastasis. These data demonstrate that Six1 is causally involved in both breast tumorigenesis and metastasis, thus raising the possibility that it may be a viable therapeutic target. However, because Six1 is highly expressed in the developing mammary gland, and because it has been implicated in the expansion of mammary stem cells, targeting Six1 as an anti-cancer therapy may have unwanted side effects in the breast.ResultsWe sought to determine the role of Six1 in mammary development using two independent mouse models. To study the effect of Six1 loss in early mammary development when Six1 is normally expressed, Six1-/- embryonic mammary glands were transplanted into Rag1-/- mice. In addition, to determine whether Six1 downregulation is required during later stages of development to allow for proper differentiation, we overexpressed Six1 during adulthood using an inducible, mammary-specific transgenic mouse model. Morphogenesis of the mammary gland occurred normally in animals transplanted with Six1-/- embryonic mammary glands, likely through the redundant functions of other Six family members such as Six2 and Six4, whose expression was increased in response to Six1 loss. Surprisingly, inappropriate expression of Six1 in the adult mammary gland, when levels are normally low to absent, did not inhibit normal mammary differentiation during pregnancy or lactation.ConclusionsSix1 is not critical for normal mammary gland development, since neither loss nor inappropriate overexpression of Six1 adversely affects normal mammary gland development or function. However, as both Six2 and Six4 levels are increased in Six1-/- mammary glands, we postulate that these Six family members are functionally redundant in the gland, as is true of many homeobox gene families. This data, in conjunction with recent findings that Six1 is capable of promoting breast cancer initiation and progression, suggest that Six1 may serve as a reasonable chemotherapeutic target in a clinical setting, particularly for those women diagnosed with breast cancer in their childbearing years.

Dataset Information

Identification and characterization of Rhox13, a novel X-linked mouse homeobox gene.

Publications

Identification and characterization of Rhox13, a novel X-linked mouse homeobox gene.

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