Eya1 and Six1 promote neurogenesis in the cranial placodes in a SoxB1-dependent fashion

Schlosser, Gerhard; Awtry, Tammy L.; Brugmann, Samantha A.; Jensen, Eric D.; Neilson, Karen M.; Ruan, Gui; Stammler, Angelika; Voelker, Doris; Yan, Bo; Zhang, Chi; Klymkowsky, Michael W.; Moody, Sally A.

doi:10.1016/j.ydbio.2008.05.523

Cited by 99 publications

(137 citation statements)

References 76 publications

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“…Indeed, Numb inheritance in daughter cells acts to inhibit Notch signaling (Chapman et al, 2006). Consistent with our results, Eya1 abrogation inhibits Notch signaling during sensory progenitor development in mammalian inner ear (Zou et al, 2008), whereas high levels of Eya1 inhibit neuronal differentiation, but expand the pool of proliferative neuronal progenitors (Schlosser et al, 2008). Our findings that genetically increasing Notch activity in Eya1 -/-lungs substantially rescues the abnormal lung epithelial phenotype in vivo ( Fig.…”

Section: Developmentsupporting

confidence: 89%

Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium

et al. 2011

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Cell polarity, mitotic spindle orientation and asymmetric division play a crucial role in the self-renewal/differentiation of epithelial cells, yet little is known about these processes and the molecular programs that control them in embryonic lung distal epithelium. Herein, we provide the first evidence that embryonic lung distal epithelium is polarized with characteristic perpendicular cell divisions. Consistent with these findings, spindle orientation-regulatory proteins Insc, LGN (Gpsm2) and NuMA, and the cell fate determinant Numb are asymmetrically localized in embryonic lung distal epithelium. Interfering with the function of these proteins in vitro randomizes spindle orientation and changes cell fate. We further show that Eya1 protein regulates cell polarity, spindle orientation and the localization of Numb, which inhibits Notch signaling. Hence, Eya1 promotes both perpendicular division as well as Numb asymmetric segregation to one daughter in mitotic distal lung epithelium, probably by controlling aPKCζ phosphorylation. Thus, epithelial cell polarity and mitotic spindle orientation are defective after interfering with Eya1 function in vivo or in vitro. In addition, in Eya1−/− lungs, perpendicular division is not maintained and Numb is segregated to both daughter cells in mitotic epithelial cells, leading to inactivation of Notch signaling. As Notch signaling promotes progenitor cell identity at the expense of differentiated cell phenotypes, we test whether genetic activation of Notch could rescue the Eya1−/− lung phenotype, which is characterized by loss of epithelial progenitors, increased epithelial differentiation but reduced branching. Indeed, genetic activation of Notch partially rescues Eya1−/− lung epithelial defects. These findings uncover novel functions for Eya1 as a crucial regulator of the complex behavior of distal embryonic lung epithelium.

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Section: Developmentsupporting

confidence: 89%

Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium

et al. 2011

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“…Interestingly, recent evidence suggests that Six1 can confer dose-dependent effects in cranial placodes during development (50). Small-to-moderate increases in the levels of homeobox gene expression are known to have substantial effects on target gene transcription with significant phenotypic consequences.…”

Section: Discussionmentioning

confidence: 99%

Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition

McCoy¹,

Iwanaga²,

Jedlicka³

et al. 2009

J. Clin. Invest.

158

180

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Six1 is a developmentally regulated homeoprotein with limited expression in most normal adult tissues and frequent misexpression in a variety of malignancies. Here we demonstrate, using a bitransgenic mouse model, that misexpression of human Six1 in adult mouse mammary gland epithelium induces tumors of multiple histological subtypes in a dose-dependent manner. The neoplastic lesions induced by Six1 had an in situ origin, showed diverse differentiation, and exhibited progression to aggressive malignant neoplasms, as is often observed in human carcinoma of the breast. Strikingly, the vast majority of Six1-induced tumors underwent an epithelial-mesenchymal transition (EMT) and expressed multiple targets of activated Wnt signaling, including cyclin D1. Interestingly, Six1 and cyclin D1 coexpression was found to frequently occur in human breast cancers and was strongly predictive of poor prognosis. We further show that Six1 promoted a stem/progenitor cell phenotype in the mouse mammary gland and in Six1-driven mammary tumors. Our data thus provide genetic evidence for a potent oncogenic role for Six1 in mammary epithelial neoplasia, including promotion of EMT and stem cell-like features.

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“…the nasal, lens, otic and taste bud placodes, as well as the hypophyseal placode), which are the precursors of sensory tissues, develop from the cephalic ectoderm and express Sox2 as a key regulator (Okubo et al, 2006;Schlosser et al, 2008;Uchikawa et al, 2011;Wood and Episkopou, 1999). All of these placodes express N-cadherin (cadherin 2, Cdh2) in a Sox2-dependent fashion during their morphogenesis (Matsumata et al, 2005).…”

Section: Sox2 In the Sensory Placodesmentioning

confidence: 99%

Sox proteins: regulators of cell fate specification and differentiation

2013

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SummarySox transcription factors play widespread roles during development; however, their versatile functions have a relatively simple basis: the binding of a Sox protein alone to DNA does not elicit transcriptional activation or repression, but requires binding of a partner transcription factor to an adjacent site on the DNA. Thus, the activity of a Sox protein is dependent upon the identity of its partner factor and the context of the DNA sequence to which it binds. In this Primer, we provide an mechanistic overview of how Sox family proteins function, as a paradigm for transcriptional regulation of development involving multi-transcription factor complexes, and we discuss how Sox factors can thus regulate diverse processes during development. Key words: HMG domain, Partner factors, Transcriptional regulation, Stem cells, Cell lineage specification IntroductionAn emerging view of transcriptional regulation in developmental processes is that transcription factor complexes, rather than single transcription factors, play a major role (Reményi et al., 2004;Verger and Duterque-Coquillaud, 2002). This idea has been pioneered, most rigorously tested and studied in a variety of developmental contexts in the case of Sox (SRY-related HMG-box) family proteins. Sox family proteins are a conserved group of transcriptional regulators (see Box 1) defined by the presence of a highly conserved highmobility group (HMG) domain that mediates DNA binding. This domain was first identified in Sry, a crucial factor involved in mammalian male sex determination (Gubbay et al., 1990;Sinclair et al., 1990). Multiple other Sox proteins have subsequently been identified and analysed. Vertebrate genomes contain ~20 Sox family members with highly divergent developmental functions, as was indicated by the initial analyses of Sox expression in embryos (Collignon et al., 1996;Uwanogho et al., 1995). Although Sox proteins are also conserved in invertebrate lineages and exert analogous regulatory functions (Phochanukul and Russell, 2010), we here confine our discussion to the vertebrate Sox family members. In this Primer, we first outline the structure and molecular activities of Sox proteins, before discussing their roles during vertebrate development. In particular, the action and function of Sox proteins will be overviewed as a paradigm for transcriptional regulation mediated by a family of transcription factors. Sox protein structureSox proteins can bind to ATTGTT or related sequence motifs through their HMG domain, which consists of three α helices (Badis et al., 2009;Kondoh and Kamachi, 2010). This binding is established by the interaction of the HMG domain with the minor groove of the DNA, which widens the minor groove and causes DNA to bend towards the major groove (Reményi et al., 2003). It is speculated that DNA bending itself may contribute to the regulatory functions of Sox proteins (Pevny and Lovell-Badge, 1997), but this has not been proved experimentally. Sox proteins are classified into groups A-H, depending on the amino acid sequ...

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Eya1 and Six1 promote neurogenesis in the cranial placodes in a SoxB1-dependent fashion

Cited by 99 publications

References 76 publications

Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium

Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium

Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition

Sox proteins: regulators of cell fate specification and differentiation

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