The Dachshund gene in development and hormone-responsive tumorigenesis

Abstract

The dachshund (dac) gene was initially described as a mutant phenotype in flies featuring extremely short legs relative to their body length. Functioning as a dominant suppressor of the ellipse mutation, a hypermorphic allele of the Epidermal Growth Factor Receptor (EGFR), the dac gene plays a key role in metazoan development, regulating ocular, limb, brain, and gonadal development. In the Drosophila eye, dac is a key component of the Retinal Determination Gene Network (RDGN) governing the normal initiation of the morphogenetic furrow and thereby eye development. Recent studies have demonstrated an important role for human DACHSHUND in tumorigenesis, in particular, breast, prostate and ovarian cancer. The molecular mechanisms by which DACH1 regulates differentiation and tumorigenesis are discussed herein. dachshund in Gonadal DevelopmentThe Retinal Determination Gene Network, RDGN, plays an important role in Drosophila gonadal development [1][2][3]. In Drosophila, the male and female genital tracts undergo patterning gene expression in homologous regions in both sexes. In this regard, wg is expressed along the anterior-posterior (AP) border, flanked by a broad stripe of dpp expression [4]. In contrast, dac is expressed in a sex-specific manner. dac function is important for development of both male and female genitalia. Male dac mutant flies have abnormal external male genital structures known as claspers, whereas female dac mutant flies have defective ovarian duct formation [4]. In the male genital disc, wg represses dac expression while dpp signaling induces it [4,5]. In contrast, wg activates dac expression while dpp represses dac expression in the female genital disc (Figure 1). The Eya protein also plays an important role in Drosophila gonad development [2,6]. eya is expressed in the somatic gonadal precursor and required for the maintenance of somatic gonadal precursor (SGP) cell fate. The function of dac as a part of the RDGN in sex determination in flies indicates the importance of this gene in development not only in Arthropods but also in mammalian models, as we will discuss later in this review. dac has also been shown to play a crucial role in Drosophila eye development (Box 1). *Corresponding Author: Richard G. Pestell, The Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, 233 South 10 th Street, Philadelphia, PA 19107, Tel: 213-503-5692; Fax: 215-503-9334, For Reprints: Cecilia.Deemer@kimmelcancercenter.org. # Authors have contributed equally to the manuscript.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public...

EYA4 Promotes Cell Proliferation Through Downregulation of p27Kip1 in Glioma

“…The Eyes absent (EYA) gene family which has been identified as a key regulator for eye development in Drosophila is now implicated in processes as disparate as organ development, DNA damage repair, tumorigenesis, angiogenesis and cancer metastasis [31,32]. EYA4, as Co-expression analysis of EYA4 and p27Kip1 in three independent glioma microarray datasets using the gene correlation module of the R2 microarray analysis and visualization platform.…”

Increased Expression of Dachshund Homolog 1 in Ovarian Cancer as a Predictor for Poor Outcome

“…During the last decade, the emerging role of DACH1 in development and tumorigenesis has been extensively documented. 16 Originally identified as one of the key members of RDGN in Drosophila, dac gene was characterized as having a key role in metazoan development, regulating ocular, limb, brain, and gonadal development. Recent studies provided compelling evidence that the members of RDGN complex are also involved in regulation of tumorigenesis.…”

Retinal determination genes function along with cell‐cell signals to regulate Drosophila eye development

“…These genes form a regulatory network whose homologs also regulate eye development in vertebrates. Many of these genes also play roles, alone and in combinations, in the development of other tissues[25–30]. There is an extensive literature on the cross-regulatory interactions among these genes which we do not review here[24,31–35].…”

“…Deep in the network, many eye genes will be secondary targets of RD genes and extracellular signals, directly regulated by transcription factors that are direct, primary targets. It will be interesting to consider what are the particular features or advantages of this multilayer network, and whether different types of network are prone to particular defects when the system breaks down, such as in cancers that overexpress RD genes[29,30]. …”