Otefin, a Nuclear Membrane Protein, Determines the Fate of Germline Stem Cells in Drosophila via Interaction with Smad Complexes

State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, 25 Beisihuanxi Road, Haidian, Beijing, 100080, China.
Developmental Cell (Impact Factor: 9.71). 05/2008; 14(4):494-506. DOI: 10.1016/j.devcel.2008.02.018
Source: PubMed


Nuclear envelope proteins play important roles in chromatin organization, gene regulation, and signal transduction; however, the physiological role of these proteins remains elusive. We found that otefin (ote), which encodes a nuclear lamin-binding protein [corrected], is essential for germline stem cell (GSC) maintenance. We show that Ote, as an intrinsic factor, is both necessary and sufficient to regulate GSC fate. Furthermore, we demonstrate that ote is required for the Dpp/BMP signaling pathway to silence bam transcription. By structure-function analysis, we demonstrate that the nuclear membrane localization of Ote is essential for its role in GSC maintenance. Finally, we show that Ote physically interacts with Medea/Smad4 at the bam silencer element to regulate GSC fate. Thus, we demonstrate that specific nuclear membrane components mediate signal-dependent transcriptional effects to control stem cell behavior.

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    • "A preponderance of RNA-mediated regulatory mechanisms rather than transcription-centric cross-regulation is a conserved hallmark of germline development. However, in addition to translation, regulation of protein stability and chromatin modifications has also been shown to influence the GSC–CB decision (Casanueva and Ferguson, 2004; Xi and Xie, 2005; Jiang et al., 2008; Xia et al., 2010, 2012; Wang et al., 2011; Barton et al., 2013; Pan et al., 2014). As differentiating cysts can be reprogrammed in vivo either upon GSC loss or during ageing to regain GSC potential (Kai and Spradling, 2004), these mechanisms may reinforce a commitment to differentiation and guarantee a long-lasting, reliable production of progeny. "
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    ABSTRACT: Stem cells give rise to tissues and organs during development and maintain their integrity during adulthood. They have the potential to self-renew or differentiate at each division. To ensure proper organ growth and homeostasis, self-renewal versus differentiation decisions need to be tightly controlled. Systematic genetic studies in Drosophila melanogaster are revealing extensive regulatory networks that control the switch between stem cell self-renewal and differentiation in the germline. These networks, which are based primarily on mutual translational repression, act via interlocked feedback loops to provide robustness to this important fate decision.
    The Journal of Cell Biology 10/2014; 207(1):13-21. DOI:10.1083/jcb.201407102 · 9.83 Impact Factor
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    • "The prevalence of the S class of germaria in all ote À / À ovaries was unexpected for several reasons . First , this phenotypic class was not reported previously ( Jiang et al . , 2008 ) , even though these studies also utilized stocks carrying the ote B279 allele . Second , we expected that a loss of bam regulation would result in 3 - day - old ovaries having fewer germ cells than 1 - day - old ovaries , because more time would have elapsed to allow differentiating egg chambers to complete development . Together , th"
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    ABSTRACT: LEM domain (LEM-D) proteins are components of an extensive protein network that assembles beneath the inner nuclear envelope. Defects in LEM-D proteins cause tissue-restricted human diseases associated with altered stem cell homeostasis. Otefin (Ote) is a Drosophila LEM-D protein that is intrinsically required for female germline stem cell (GSC) maintenance. Previous studies linked Ote loss with transcriptional activation of the key differentiation gene bag-of-marbles (bam), leading to the model in which Ote tethers the bam gene to the nuclear periphery for gene silencing. Using genetic and phenotypic analyses of multiple ote(-/-) backgrounds, we obtained evidence that is inconsistent with this model. We show that bam repression is maintained in ote(-/-) GSCs and that germ cell loss persists in ote(-/-), bam(-/-) mutants, together demonstrating that GSC loss is independent of bam transcription. We show that the primary defect in ote(-/-) GSCs is a block of differentiation, which ultimately leads to germ cell death.
    Developmental Cell 06/2013; 25(6):645-654. DOI:10.1016/j.devcel.2013.05.023 · 9.71 Impact Factor
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    • "In addition, several LEM domain proteins bind to and regulate transcription factors and signaling molecules such as b-catenin (Markiewicz et al., 2006), Smads (Lin et al., 2005; Pan et al., 2005; Jiang et al., 2008), germ-cell-less (gcl) (Nili et al., 2001; Holaska et al., 2003) and retinoblastoma protein (Markiewicz et al., 2002; Dorner et al., 2006). Mutations in genes encoding emerin, MAN1 and LAP2a have been linked to a number of human pathologies (Vlcek and Foisner, 2007; Wagner and Krohne, 2007; Worman and Bonne, 2007; Chi et al., 2009), reflecting their multiple and diverse functions. "
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    ABSTRACT: The LEM domain (for lamina-associated polypeptide, emerin, MAN1 domain) defines a group of nuclear proteins that bind chromatin through interaction of the LEM motif with the conserved DNA crosslinking protein, barrier-to-autointegration factor (BAF). Here, we describe a LEM protein annotated in databases as 'Ankyrin repeat and LEM domain-containing protein 1' (Ankle1). We show that Ankle1 is conserved in metazoans and contains a unique C-terminal GIY-YIG motif that confers endonuclease activity in vitro and in vivo. In mammals, Ankle1 is predominantly expressed in hematopoietic tissues. Although most characterized LEM proteins are components of the inner nuclear membrane, ectopic Ankle1 shuttles between cytoplasm and nucleus. Ankle1 enriched in the nucleoplasm induces DNA cleavage and DNA damage response. This activity requires both the catalytic C-terminal GIY-YIG domain and the LEM motif, which binds chromatin via BAF. Hence, Ankle1 is an unusual LEM protein with a GIY-YIG-type endonuclease activity in higher eukaryotes.
    Journal of Cell Science 03/2012; 125(Pt 4):1048-57. DOI:10.1242/jcs.098392 · 5.43 Impact Factor
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