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1.
PLoS Biol ; 21(1): e3001924, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36649236

RESUMO

Tissue-specific transcription factors (TFs) control the transcriptome through an association with noncoding regulatory regions (cistromes). Identifying the combination of TFs that dictate specific cell fate, their specific cistromes and examining their involvement in complex human traits remain a major challenge. Here, we focus on the retinal pigmented epithelium (RPE), an essential lineage for retinal development and function and the primary tissue affected in age-related macular degeneration (AMD), a leading cause of blindness. By combining mechanistic findings in stem-cell-derived human RPE, in vivo functional studies in mice and global transcriptomic and proteomic analyses, we revealed that the key developmental TFs LHX2 and OTX2 function together in transcriptional module containing LDB1 and SWI/SNF (BAF) to regulate the RPE transcriptome. Importantly, the intersection between the identified LHX2-OTX2 cistrome with published expression quantitative trait loci, ATAC-seq data from human RPE, and AMD genome-wide association study (GWAS) data, followed by functional validation using a reporter assay, revealed a causal genetic variant that affects AMD risk by altering TRPM1 expression in the RPE through modulation of LHX2 transcriptional activity on its promoter. Taken together, the reported cistrome of LHX2 and OTX2, the identified downstream genes and interacting co-factors reveal the RPE transcription module and uncover a causal regulatory risk single-nucleotide polymorphism (SNP) in the multifactorial common blinding disease AMD.


Assuntos
Degeneração Macular , Canais de Cátion TRPM , Humanos , Camundongos , Animais , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Estudo de Associação Genômica Ampla , Proteômica , Degeneração Macular/genética , Degeneração Macular/metabolismo , Diferenciação Celular , Epitélio/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Canais de Cátion TRPM/genética , Fatores de Transcrição Otx/genética , Fatores de Transcrição Otx/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo
2.
Dev Biol ; 468(1-2): 80-92, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32950463

RESUMO

The interplay between signaling molecules and transcription factors during retinal development is key to controlling the correct number of retinal cell types. Zeb2 (Sip1) is a zinc-finger multidomain transcription factor that plays multiple roles in central and peripheral nervous system development. Haploinsufficiency of ZEB2 causes Mowat-Wilson syndrome, a congenital disease characterized by intellectual disability, epilepsy and Hirschsprung disease. In the developing retina, Zeb2 is required for generation of horizontal cells and the correct number of interneurons; however, its potential function in controlling gliogenic versus neurogenic decisions remains unresolved. Here we present cellular and molecular evidence of the inhibition of Müller glia cell fate by Zeb2 in late stages of retinogenesis. Unbiased transcriptomic profiling of control and Zeb2-deficient early-postnatal retina revealed that Zeb2 functions in inhibiting Id1/2/4 and Hes1 gene expression. These neural progenitor factors normally inhibit neural differentiation and promote Müller glia cell fate. Chromatin immunoprecipitation (ChIP) supported direct regulation of Id1 by Zeb2 in the postnatal retina. Reporter assays and ChIP analyses in differentiating neural progenitors provided further evidence that Zeb2 inhibits Id1 through inhibition of Smad-mediated activation of Id1 transcription. Together, the results suggest that Zeb2 promotes the timely differentiation of retinal interneurons at least in part by repressing BMP-Smad/Notch target genes that inhibit neurogenesis. These findings show that Zeb2 integrates extrinsic cues to regulate the balance between neuronal and glial cell types in the developing murine retina.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Células Ependimogliais/metabolismo , Interneurônios/metabolismo , Retina/embriologia , Transdução de Sinais , Proteínas Smad/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Camundongos , Camundongos Transgênicos , Proteínas Smad/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
3.
Int J Dev Biol ; 61(3-4-5): 225-234, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28621420

RESUMO

The development of the eye has been a topic of extensive investigation, from the early studies on tissue induction to more recent breakthroughs in resolving the mechanism regulating progenitor patterning and their gradual and coordinated differentiation into diverse tissue types that function together throughout life. Among the ocular tissue types, the retinal pigmented epithelium (RPE) is at the forefront of developmental biology and stem cell research. The growing interest in this lineage stems from its importance for photoreceptor function as well as from its requirement during embryogenesis for the development of the photoreceptors and the choroid. Indeed mutations in RPE genes and epigenetic changes that occur during aging are the cause of monogenic as well as multifactorial retinal diseases. Importantly, the RPE is readily generated from stem cells, and these stem cell-derived RPE cells are currently being tested in clinical trials for transplantation in cases of retinal dystrophies; they also constitute an important model to study developmental processes in vitro. This review summarizes recent advances in our understanding of RPE development and its requirement for the development of photoreceptors and choroidal vasculature. We discuss the contribution of basic findings to therapeutic applications and the future challenges in uncovering developmental processes and mimicking them ex vivo to further advance research and therapy of retinal disorders.


Assuntos
Biologia do Desenvolvimento/tendências , Redes Reguladoras de Genes , Epitélio Pigmentado da Retina/embriologia , Pesquisa Translacional Biomédica/tendências , Animais , Diferenciação Celular , Corioide/metabolismo , Desenvolvimento Embrionário , Epigênese Genética , Humanos , Retina/embriologia , Degeneração Retiniana , Epitélio Pigmentado da Retina/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo
4.
Oncotarget ; 8(16): 27380-27392, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28423708

RESUMO

Advanced ovarian cancer is an incurable disease. Thus, novel therapies are required. We wished to identify new therapeutic targets for ovarian cancer. ShRNA screen performed in 42 ovarian cancer cell lines identified the centriolar replication factor STIL as an essential gene for ovarian cancer cells. This was verified in-vivo in orthotopic human ovarian cancer mouse models. STIL depletion by administration of siRNA in neutral liposomes resulted in robust anti-tumor effect that was further enhanced in combination with cisplatin. Consistent with this finding, STIL depletion enhanced the extent of DNA double strand breaks caused by DNA damaging agents. This was associated with centrosomal depletion, ongoing genomic instability and enhanced formation of micronuclei. Interestingly, the ongoing DNA damage was not associated with reduced DNA repair. Indeed, we observed that depletion of STIL enhanced canonical homologous recombination repair and increased BRCA1 and RAD51 foci in response to DNA double strand breaks. Thus, inhibition of STIL significantly enhances the efficacy of DNA damaging chemotherapeutic drugs in treatment of ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Histonas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Terapia de Alvo Molecular , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Interferência de RNA , RNA Interferente Pequeno/genética , Reparo de DNA por Recombinação , Transdução de Sinais , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Development ; 143(22): 4182-4192, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27697904

RESUMO

The Lim domain-binding proteins are key co-factor proteins that assemble with LIM domains of the LMO/LIM-HD family to form functional complexes that regulate cell proliferation and differentiation. Using conditional mutagenesis and comparative phenotypic analysis, we analyze the function of Ldb1 and Ldb2 in mouse retinal development, and demonstrate overlapping and specific functions of both proteins. Ldb1 interacts with Lhx2 in the embryonic retina and both Ldb1 and Ldb2 play a key role in maintaining the pool of retinal progenitor cells. This is accomplished by controlling the expression of the Vsx2 and Rax, and components of the Notch and Hedgehog signaling pathways. Furthermore, the Ldb1/Ldb2-mediated complex is essential for generation of early-born photoreceptors through the regulation of Rax and Crx. Finally, we demonstrate functional redundancy between Ldb1 and Ldb2. Ldb1 can fully compensate the loss of Ldb2 during all phases of retinal development, whereas Ldb2 alone is sufficient to sustain activity of Lhx2 in both early- and late-stage RPCs and in Müller glia. By contrast, loss of Ldb1 disrupts activity of the LIM domain factors in neuronal precursors. An intricate regulatory network exists that is mediated by Ldb1 and Ldb2, and promotes RPC proliferation and multipotency; it also controls specification of mammalian retina cells.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Proteínas com Domínio LIM/fisiologia , Organogênese/genética , Retina/embriologia , Fatores de Transcrição/fisiologia , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes/fisiologia , Mamíferos/embriologia , Mamíferos/genética , Camundongos , Camundongos Transgênicos , Retina/citologia , Retina/metabolismo , Células-Tronco/fisiologia
6.
Sci Rep ; 6: 24296, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-27075531

RESUMO

The STIL protein is essential for centriole replication and for the non-templated, de novo centriole biogenesis that is required for mammalian embryogenesis. Here we performed quantitative biophysical and structural analysis of the central short coiled coil domain (CCD) of STIL that is critical for its function. Using biophysical, biochemical and cell biology approaches, we identified the specific residues in the CCD that mediate the oligomerization, centrosomal localization and protein interactions of STIL. We characterized the structural properties of the coiled coil peptide using circular dichroism spectroscopy and size exclusion chromatography. We identified two regions in this domain, containing eight hydrophobic residues, which mediate the coiled coil oligomerization. Mutations in these residues destabilized the coiled coil thermodynamically but in most cases did not affect its secondary structure. Reconstituting mouse embryonic fibroblasts lacking endogenous Stil, we show that STIL oligomerization mediated by these residues is not only important for the centrosomal functions of STIL during the canonical duplication process but also for de-novo formation of centrosomes.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Centrossomo/metabolismo , Multimerização Proteica , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Animais , Fenômenos Biofísicos , Células Cultivadas , Cromatografia em Gel , Dicroísmo Circular , Humanos , Camundongos , Conformação Proteica , Mapeamento de Interação de Proteínas , Transporte Proteico , Proteína 1 de Leucemia Linfocítica Aguda de Células T
7.
Chem Sci ; 7(7): 4140-4147, 2016 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30155058

RESUMO

Binding of metal ions is an important regulatory mechanism in proteins. Specifically, Zn2+ binding to disordered regions commonly induces a disorder to order transition and gain of structure or oligomerization. Here we show that simultaneous binding of Zn2+ ions has different effects on structured and disordered domains in the same multidomain protein. The centrosomal STIL protein bound Zn2+ ions via both its structured N-terminal domain (NTD) and disordered central region (IDR). Zn2+ binding induced structural rearrangement of the structured NTD but promoted oligomerization of the IDR. We suggest that by binding Zn2+ STIL acquires a different conformation, which allows its oligomerization and induces its activity. Sequence alignment of the oligomerization region revealed a new suggested motif, SxKxS/SxHxS/SxLxS, which may participate in STIL oligomerization. Binding of the same metal ion through a disordered and a structured domain in the same protein is a property that may have implications in regulating the protein activity. By doing so, the protein achieves two parallel outcomes: structural changes and oligomerization that can take place together. Our results describe a new important role of the delicate interplay between structure and intrinsic disorder in proteins.

8.
Cell Cycle ; 13(18): 2859-68, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25486474

RESUMO

Although most animal cells contain centrosomes, consisting of a pair of centrioles, their precise contribution to cell division and embryonic development is unclear. Genetic ablation of STIL, an essential component of the centriole replication machinery in mammalian cells, causes embryonic lethality in mice around mid gestation associated with defective Hedgehog signaling. Here, we describe, by focused ion beam scanning electron microscopy, that STIL(-/-) mouse embryos do not contain centrioles or primary cilia, suggesting that these organelles are not essential for mammalian development until mid gestation. We further show that the lack of primary cilia explains the absence of Hedgehog signaling in STIL(-/-) cells. Exogenous re-expression of STIL or STIL microcephaly mutants compatible with human survival, induced non-templated, de novo generation of centrioles in STIL(-/-) cells. Thus, while the abscence of centrioles is compatible with mammalian gastrulation, lack of centrioles and primary cilia impairs Hedgehog signaling and further embryonic development.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Centríolos/metabolismo , Cílios/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Centríolos/ultraestrutura , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Embrião de Mamíferos/ultraestrutura , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Microcefalia/patologia , Centro Organizador dos Microtúbulos/metabolismo , Mutação/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Proteína 1 de Leucemia Linfocítica Aguda de Células T
9.
FEBS Lett ; 588(21): 3808-15, 2014 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-25218436

RESUMO

The Nck adapter protein is involved in key cellular functions, such as actin polymerization and reorganization, serving as a molecular bridge between the surface complex essential for foreign antigen recognition, the T-cell antigen receptor (TCR), and the actin machinery. However, the mechanisms regulating Nck expression and functions are unknown. In this study, we revealed Nck negative regulation and demonstrated that Nck is ubiquitylated following cellular activation. We identified the molecular determinants and mediators involved in this process. Our data suggest that Nck ubiquitylation might serve as a mechanism controlling Nck-mediated effector functions during cellular activation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Regulação para Baixo , Proteínas Oncogênicas/metabolismo , Ubiquitinação , Actinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Adesão Celular , Inativação Gênica , Células HEK293 , Humanos , Células Jurkat , Mutação , Proteínas Oncogênicas/química , Proteínas Oncogênicas/deficiência , Proteínas Oncogênicas/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteínas Proto-Oncogênicas c-cbl/metabolismo , RNA Interferente Pequeno/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Domínios de Homologia de src
10.
Chem Commun (Camb) ; 50(40): 5245-7, 2014 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-24022511

RESUMO

The STIL protein participates in mitosis and malignant transformation by regulating centrosomal duplication. Using biophysical methods we studied the structure and interactions of STIL. We revealed that its central domain is intrinsically disordered and mediates protein-protein interactions of STIL. The intrinsic disorder may provide STIL with the conformational flexibility required for its multitude binding.


Assuntos
Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Dicroísmo Circular , Polarização de Fluorescência , Humanos , Proteínas de Ligação a Poli-ADP-Ribose , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Ubiquitina-Proteína Ligases
11.
J Cell Sci ; 126(Pt 15): 3259-62, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23908378

RESUMO

Located in the 16th century Wiston House in West Sussex, UK, the 'Building a Centrosome' Workshop was organised by The Company of Biologists and chaired by Fanni Gergely and David Glover (University of Cambridge). Held in March 2013, the Workshop gathered together many of the leaders in the field of centrosome biology, as well as postdocs and students who were given the opportunity to meet and interact with many of the scientists who inspired their early careers. The diverse range of speakers provided a multi-disciplinary forum for the exchange of ideas, and gave fresh impetus to tackling outstanding questions related to centrosome biology. Here, we provide an overview of the meeting and highlight the main themes that were discussed.


Assuntos
Centrossomo/fisiologia , Animais , Humanos
12.
Mol Cell Biol ; 32(15): 3153-63, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22665495

RESUMO

The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of actin dynamics during cell motility and adhesion, and mutations in its gene are responsible for Wiskott-Aldrich syndrome (WAS). Here, we demonstrate that WASp is ubiquitylated following T-cell antigen receptor (TCR) activation. WASp phosphorylation at tyrosine 291 results in recruitment of the E3 ligase Cbl-b, which, together with c-Cbl, carries out WASp ubiquitylation. Lysine residues 76 and 81, located at the WASp WH1 domain, which contains the vast majority of WASp gene mutations, serve as the ubiquitylation sites. Disruption of WASp ubiquitylation causes WASp accumulation and alters actin dynamics and the formation of actin-dependent structures. Our data suggest that regulated degradation of activated WASp might be an efficient strategy by which the duration and localization of actin rearrangement and the intensity of T-cell activation are controlled.


Assuntos
Citoesqueleto de Actina/metabolismo , Linfócitos T/imunologia , Proteína da Síndrome de Wiskott-Aldrich/metabolismo , Citoesqueleto de Actina/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adesão Celular , Linhagem Celular , Movimento Celular , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Células HEK293 , Humanos , Células Jurkat , Ativação Linfocitária/imunologia , Fosforilação , Proteínas Proto-Oncogênicas c-cbl/genética , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Ubiquitinação , Proteína da Síndrome de Wiskott-Aldrich/biossíntese , Proteína da Síndrome de Wiskott-Aldrich/genética
13.
J Cell Sci ; 125(Pt 5): 1353-62, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22349705

RESUMO

Centrioles are key structural elements of centrosomes and primary cilia. In mammals, only a few proteins including PLK4, CPAP (CENPJ), SAS6, CEP192, CEP152 and CEP135 have thus far been identified to be required for centriole duplication. STIL (SCL/TAL1 interrupting locus, also known as SIL) is a centrosomal protein that is essential for mouse and zebrafish embryonic development and mutated in primary microcephaly. Here, we show that STIL localizes to the pericentriolar material surrounding parental centrioles. Its overexpression results in excess centriole formation. siRNA-mediated depletion of STIL leads to loss of centrioles and abrogates PLK4-induced centriole overduplication. Additionally, we show that STIL is necessary for SAS6 recruitment to centrioles, suggesting that it is essential for daughter centriole formation, interacts with the centromere protein CPAP and rapidly shuttles between the cytoplasm and centrioles. Consistent with the requirement of centrioles for cilia formation, Stil(-/-) mouse embryonic fibroblasts lack primary cilia--a phenotype that can be reverted by restoration of STIL expression. These findings demonstrate that STIL is an essential component of the centriole replication machinery in mammalian cells.


Assuntos
Centríolos/metabolismo , Cílios/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ciclo Celular , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Divisão Celular/fisiologia , Linhagem Celular , Centríolos/genética , Centrossomo/fisiologia , Citoplasma/fisiologia , Células HEK293 , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno
14.
J Cell Sci ; 124(Pt 4): 532-9, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21245198

RESUMO

Stil (Sil, SCL/TAL1 interrupting locus) is a cytosolic and centrosomal protein expressed in proliferating cells that is required for mouse and zebrafish neural development and is mutated in familial microcephaly. Recently the Drosophila melanogaster ortholog of Stil was found to be important for centriole duplication. Consistent with this finding, we report here that mouse embryonic fibroblasts lacking Stil are characterized by slow growth, low mitotic index and absence of clear centrosomes. We hypothesized that Stil regulates mitosis through the tumor suppressor Chfr, an E3 ligase that blocks mitotic entry in response to mitotic stress. Mouse fibroblasts lacking Stil by genomic or RNA interference approaches, as well as E9.5 Stil(-/-) embryos, express high levels of the Chfr protein and reduced levels of the Chfr substrate Plk1. Exogenous expression of Stil, knockdown of Chfr or overexpression of Plk1 reverse the abnormal mitotic phenotypes of fibroblasts lacking Stil. We further demonstrate that Stil increases Chfr auto-ubiquitination and reduces its protein stability. Thus, Stil is required for centrosome organization, entry into mitosis and cell proliferation, and these functions are at least partially mediated by Chfr and its targets. This is the first identification of a negative regulator of the Chfr mitotic checkpoint.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Centrossomo/metabolismo , Regulação para Baixo , Mitose , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Camundongos Knockout , Proteínas de Ligação a Poli-ADP-Ribose , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética
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