Fani Papagiannouli | University of Kent (original) (raw)

Papers by Fani Papagiannouli

In the past decade, the importance of the niche to provide regulatory inputs to balance stem cell... more In the past decade, the importance of the niche to provide regulatory inputs to balance stem cell self-renewal and differentiation has become clear. However, the regulatory interplay between stem cells and their niche at the whole genome level is still poorly understood. To elucidate the mechanisms controlling stem cells and their progenies as they progress through their developmental program at the transcriptional level, we recorded the regulatory program of two independent cell lineages in the Drosophila testis stem cell model. To this end, we identified genes active in the soma or germline as well as genome-wide binding profiles of two essential transcription factors, Zfh-1 and Abd-A, expressed in somatic support cells and crucial for fate acquisition of both cell lineages. Our data identified key roles for TOR signalling, signal processing V-ATPase proton pumps and the nuclear transport engaged nucleoporins and we demonstrate their importance in controlling germline maintenance,...

SUMMARYNucleocytoplasmic communication is crucial for proper cell function and coordination of in... more SUMMARYNucleocytoplasmic communication is crucial for proper cell function and coordination of intrinsic cues with signaling responses emanating from the neighboring cells and the local tissue microenvironment. In the Drosophila male germline system, germ cells proliferate and progressively differentiate enclosed in supportive somatic cyst cells, forming a small cyst, the functional unit of differentiation. Here we show that the peripheral nucleoporins Nup62, Nup214 and Nup88, and the exportin Emb are critically required in cyst cells to maintain cyst cell survival and germline encapsulation in order to protect cyst cell-germline communication and promote germ cell differentiation. Knockdown of nup62, emb, nup214 or nup88 in cyst cells leads to cell-autonomous defects in mRNA export, and cell non-autonomous overproliferation of early germ cells in the absence of cyst cell-derived differentiation signals. Suppression of apoptosis can reverse cyst cell elimination and partially restor...

Gene Expression Patterns, May 31, 2003

The tumour suppressor gene scribble (scrib) is required for epithelial polarity and growth contro... more The tumour suppressor gene scribble (scrib) is required for epithelial polarity and growth control in Drosophila, and encodes two protein isoforms. Here, we report the pattern of Scrib1 synthesis in pole cells and embryonic gonads. We found that Scrib1 synthesis became strongly enhanced in pole cells at the time of gonad formation and was also detectable in cortical domains of gonadal mesodermal cells adjacent to pole cells. Scrib1 synthesis in mesodermal cells was independent of pole cells and occurred in agametic valois and capsuléen embryonic gonads. In contrast, Scrib1 synthesis in pole cells required contact with gonadal mesodermal cells as revealed by the absence of Scrib1 in wunen or tinman-zinc finger homeodomain-1 pseudo-gonads made only of aggregated pole cells.

Stem Cell Biology and Regenerative Medicine, 2015

Current topics in developmental biology, 2015

Apoptosis is a cellular suicide program, which is on the one hand used to remove superfluous cell... more Apoptosis is a cellular suicide program, which is on the one hand used to remove superfluous cells thereby promoting tissue or organ morphogenesis. On the other hand, the programmed killing of cells is also critical when potentially harmful cells emerge in a developing or adult organism thereby endangering survival. Due to its critical role apoptosis is tightly controlled, however so far, its regulation on the transcriptional level is less studied and understood. Hox genes, a highly conserved gene family encoding homeodomain transcription factors, have crucial roles in development. One of their prominent functions is to shape animal body plans by eliciting different developmental programs along the anterior-posterior axis. To this end, Hox proteins transcriptionally regulate numerous processes in a coordinated manner, including cell-type specification, differentiation, motility, proliferation as well as apoptosis. In this review, we will focus on how Hox proteins control organismal ...

Mechanisms of Development, 2015

A fundamental question is how complex structures are maintained after their initial specification... more A fundamental question is how complex structures are maintained after their initial specification. Stem cells reside in a specialized microenvironment, called niche, which provides essential signals controlling stem cell behavior. We addressed this question by studying the Drosophila male stem cell niche, called the hub. Once specified, the hub cells need to maintain their position and architectural integrity through embryonic, larval and pupal stages of testis organogenesis and during adult life. The Hox gene Abd-B, in addition to its described role in male embryonic gonads, maintains the architecture and positioning of the larval hub from the germline by affecting integrin localization in the neighboring somatic cyst cells. We find that the AbdB-Boss/Sev cascade affects integrin independent of Talin, while genetic interactions depict integrin as the central downstream player in this system. Focal adhesion and integrin-adaptor proteins within the somatic stem cells and cyst cells, such as Paxillin, Pinch and Vav, also contribute to proper hub integrity and positioning. During adult stages, hub positioning is controlled by Abd-B activity in the outer acto-myosin sheath, while Abd-B expression in adult spermatocytes exerts no effect on hub positioning and integrin localization. Our data point at a cell- and stage-specific function of Abd-B and suggest that the occurrence of new cell types and cell interactions in the course of testis organogenesis made it necessary to adapt the whole system by reusing the same players for male stem cell niche positioning and integrity in an alternative manner.

ABSTRACT Heidelberg, University, Diss., 2003.

Tumor Suppressor Genes, 2012

Stem Cell Reports, 2019

Tissue homeostasis and repair relies on proper communication of stem cells and their differentiat... more Tissue homeostasis and repair relies on proper communication of stem cells and their differentiating daughters with the local tissue microenvironment. In the Drosophila male germline adult stem cell lineage, germ cells proliferate and progressively differentiate enclosed in supportive somatic cyst cells, forming a small organoid, the functional unit of differentiation. Here we show that cell polarity and vesicle trafficking influence signal transduction in cyst cells, with profound effects on the germ cells they enclose. Our data suggest that the cortical components Dlg, Scrib, Lgl and the clathrin-mediated endocytic (CME) machinery downregulate epidermal growth factor receptor (EGFR) signaling. Knockdown of dlg, scrib, lgl, or CME components in cyst cells resulted in germ cell death, similar to increased signal transduction via the EGFR, while lowering EGFR or downstream signaling components rescued the defects. This work provides insights into how cell polarity and endocytosis cooperate to regulate signal transduction and sculpt developing tissues.

Cell Reports, 2018

The niche critically controls stem cell behavior, but its regulatory input at the whole-genome le... more The niche critically controls stem cell behavior, but its regulatory input at the whole-genome level is poorly understood. We elucidated transcriptional programs of the somatic and germline lineages in the Drosophila testis and genome-wide binding profiles of Zfh-1 and Abd-A expressed in somatic support cells and crucial for fate acquisition of both cell lineages. We identified key roles of nucleoporins and V-ATPase proton pumps and demonstrate their importance in controlling germline development from the support side. To make our dataset publicly available, we generated an interactive analysis tool, which uncovered conserved core genes of adult stem cells across species boundaries. We tested the functional relevance of these genes in the Drosophila testis and intestine and found a high frequency of stem cell defects. In summary, our dataset and interactive platform represent versatile tools for identifying gene networks active in diverse stem cell types.

Fly, 2010

Gamete development requires a coordinated soma-germ line interaction that ensures renewal and dif... more Gamete development requires a coordinated soma-germ line interaction that ensures renewal and differentiation of germline and somatic stem cells. The physical contact between the germline and somatic cell populations is crucial because it allows the exchange of diffusible signals among them. The tumor suppressor gene discs large (dlg) encodes a septate junction protein with functions in epithelial cell polarity, asymmetric neuroblast division and formation of neuromuscular junctions. Our recent work reveals a new role of dlg in the Drosophila testis, as mutations in dlg lead to testis defects and cell death. Dlg is required throughout spermatogenesis in the somatic lineage and its localization changes from a uniform distribution along the plasma membrane of somatic cells in the testis apex, to a restricted localization on the distally located somatic cell in growing cysts. The extensive defects in dlg testis underline the importance of the somatic cells in the establishment and maintenance of the male stem cell niche and somatic cell differentiation. Here, we discuss our latest findings on the role of dlg in the Drosophila testis, supporting the view that junction proteins are dynamic structures, which can provide guiding cues to recruit scaffold proteins or other signaling molecules.

A fundamental question in biology is how complex structures are maintained after their initial sp... more A fundamental question in biology is how complex structures are maintained after their initial specification. We address this question by reviewing the role of the Hox gene Abd-B in Drosophila testis organogenesis, which proceeds through embryonic, larval and pupal stages to reach maturation in adult stages. The data presented in this review highlight a cell- and stage-specific function of Abd-B, since the mechanisms regulating stem cell niche positioning and architecture at different stages seem to be different despite the employment of similar factors. In addition to its described role in the male embryonic gonads, sustained activity of Abd-B in the pre-meiotic germline spermatocytes during larval stages is required to maintain the architecture of the stem cell niche by regulating βPS-integrin localization in the neighboring somatic cyst cells. Loss of Abd-B is associated with cell non-autonomous effects within the niche, leading to a dramatic reduction of pre-meiotic cell populations in adult testes. Identification of Abd-B target genes revealed that Abd-B mediates its effects by controlling the activity of the sevenless ligand Boss via its direct targets Src42A and Sec63. During adult stages, when testis morphogenesis is completed with the addition of the acto-myosin sheath originating from the genital disc, stem cell niche positioning and integrity are regulated by Abd-B activity in the acto-myosin sheath whereas integrin acts in an Abd-B independent way. It seems that the occurrence of new cell types and cell interactions in the course of testis organogenesis made it necessary to adapt the system to the new cellular conditions by reusing the same players for testis stem cell niche positioning in an alternative manner.

Int J Dev Biol. , 2013

Interest in the mechanism leading to the formation of the germline and its differentiation during... more Interest in the mechanism leading to the formation of the germline and its differentiation during Drosophila development, initiated even as soon as the first ever cloned tumour suppressor gene in Drosophila, the lethal (2) giant larvae (lgl), had been identified. Further work has shown that the lgl, as well as discs large-1 (dlg) and scribble (scrib) tumor suppressor genes code for scaffolding proteins associated with either the cytoskeletal matrix or the septate junctions that act in common pathways in various tissues. This study analysed the role of Dlg, Scrib and Lgl in the embryonic gonads and testis of Drosophila melanogaster. Loss of scrib, dlg and lgl had no effect on gonad formation, but Dlg and Scrib in the gonadal mesoderm acted critically in the somatic wrapping of the pole cells and the internal structure of the Drosophila embryonic gonads. Dlg also affected the incorporation of the male-specific Sox100B positive mesodermal cells into the male embryonic gonads, yet Sox100B expression in dlg testis remained unaffected. Analysis at later stages revealed that scrib and lgl expression in the somatic lineage of the Drosophila tes-tis, similar to what was previously shown for dlg, was indispensable for testis development and homeostasis, as depletion of these genes resulted in extensive testes defects. The data presented here emphasize the somatic requirement of Scrib, Dlg and Lgl in embryonic gonads, as well as in the Drosophila testis that underlines the importance of the somatic lineage in the establishment and maintenance of testis formation throughout successive developmental stages.

Developmental Cell, 2014

Proper niche architecture is critical for stem cell function, yet only few upstream regulators ar... more Proper niche architecture is critical for stem cell function, yet only few upstream regulators are known. Here, we report that the Hox transcription factor Abdominal-B (Abd-B), active in premeiotic spermatocytes of Drosophila testes, is essential for positioning the niche to the testis anterior by regulating integrin in neighboring somatic cyst cells. Abd-B also non-cell-autonomously controls critical features within the niche, including centrosome orientation and division rates of germline stem cells. By using genome-wide binding studies, we find that Abd-B mediates its effects on integrin localization by directly controlling at multiple levels the signaling activity of the Sev ligand Boss via its direct targets src42A and sec63, two genes involved in protein trafficking and recycling. Our data show that Abd-B, through local signaling between adjucent cell types, provides positional cues for integrin localization, which is critical for placement of the distant stem cell niche and stem cell activity.

Cell Research, 2009

Gonad development requires a coordinated soma-germline interaction that ensures renewal and diffe... more Gonad development requires a coordinated soma-germline interaction that ensures renewal and differentiation of germline and somatic stem cells to ultimately produce mature gametes. The Drosophila tumour suppressor gene discs large (dlg) encodes a septate junction protein functioning during epithelial polarization, asymmetric neuroblast division , and formation of neuromuscular junctions. Here, we report the role of dlg in testis development and its critical function in somatic cyst cells (SCCs). In these cells dlg is primarily required for their survival and expansion, and contributes to spermatocyte cyst differentiation. Cell death primarily occurred in SCCs at the end of spermatogo-nial amplification at a time when Dlg becomes restricted in wild-type (wt) testes to the distal somatic cells capping the growing spermatocyte cysts. RNAi depletion of dlg transcripts in early SCCs fully prevented testis development, whereas depletion in late SCCs resulted in a breakdown of spermatocyte cyst structure and germ cell individualiza-tion. Specific dlg expression in SCCs resulted in developmental rescue of dlg mutant testes, whereas its expression in germ cells exerted no such effect. dlg overexpression in wt testes led to spermatocyte cyst expansion at the expense of spermatogonial cysts. Our data demonstrate that dlg is essentially required in SCCs for their survival, expansion, and differentiation, and for the encapsulation of the germline cells.