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1.
Nature ; 625(7993): 126-133, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38123680

RESUMEN

Chemical signalling is the primary means by which cells communicate in the embryo. The underlying principle refers to a group of ligand-producing cells and a group of cells that respond to this signal because they express the appropriate receptors1,2. In the zebrafish embryo, Wnt5b binds to the receptor Ror2 to trigger the Wnt-planar cell polarity (PCP) signalling pathway to regulate tissue polarity and cell migration3,4. However, it remains unclear how this lipophilic ligand is transported from the source cells through the aqueous extracellular space to the target tissue. In this study, we provide evidence that Wnt5b, together with Ror2, is loaded on long protrusions called cytonemes. Our data further suggest that the active Wnt5b-Ror2 complexes form in the producing cell and are handed over from these cytonemes to the receiving cell. Then, the receiving cell has the capacity to initiate Wnt-PCP signalling, irrespective of its functional Ror2 receptor status. On the tissue level, we further show that cytoneme-dependent spreading of active Wnt5b-Ror2 affects convergence and extension in the zebrafish gastrula. We suggest that cytoneme-mediated transfer of ligand-receptor complexes is a vital mechanism for paracrine signalling. This may prompt a reevaluation of the conventional concept of characterizing responsive and non-responsive tissues solely on the basis of the expression of receptors.


Asunto(s)
Seudópodos , Receptores Huérfanos Similares al Receptor Tirosina Quinasa , Proteínas Wnt , Pez Cebra , Animales , Gástrula/citología , Gástrula/embriología , Gástrula/metabolismo , Ligandos , Proteínas Wnt/metabolismo , Vía de Señalización Wnt/fisiología , Pez Cebra/embriología , Pez Cebra/metabolismo , Polaridad Celular , Movimiento Celular , Seudópodos/metabolismo , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Comunicación Paracrina
2.
Proc Natl Acad Sci U S A ; 120(39): e2217612120, 2023 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-37722040

RESUMEN

Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment influencing cancer progression. Besides shaping the extracellular matrix, these fibroblasts provide signaling factors to facilitate tumor survival and alter tumor behavior. In gastric cancer, one crucial signaling pathway influencing invasion and metastasis is the Wnt/Planar Cell Polarity (PCP) signaling. The crucial PCP ligand in this context is WNT5A, which is produced by the CAFs, and gastric cancer cells react upon this signal by enhanced polarized migration. Why gastric cancer cells respond to this signal is still unclear, as their expression level for the central WNT5A receptor, ROR2, is very low. Here, we show that CAFs display long and branched filopodia that form an extensive, complex network engulfing gastric cancer cells, such as the gastric cancer cell line AGS. CAFs have a significantly higher expression level of ROR2 than normal gastric fibroblasts and AGS cells. By high-resolution imaging, we observe a direct transfer of fluorescently tagged ROR2 from CAF to AGS cells by signaling filopodia, known as cytonemes. Surprisingly, we find that the transferred ROR2 complexes can activate Wnt/JNK signaling in AGS cells. Consistently, blockage of ROR2 function in the CAFs leads to reduced paracrine Wnt/JNK signaling, cell polarization, and migration of the receiving AGS cells. Complementary, enhanced migration via paracrine ROR2 transfer was observed in a zebrafish in vivo model. These findings demonstrate a fresh role for cytoneme-mediated signaling in the tumor microenvironment. Cytonemes convey Wnt receptors from CAFs to gastric cancer cells, allowing them to respond to Wnt/PCP signals.


Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias Gástricas , Animales , Neoplasias Gástricas/genética , Microambiente Tumoral , Vía de Señalización Wnt , Pez Cebra , Humanos , Línea Celular Tumoral
3.
PLoS Comput Biol ; 16(6): e1007417, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32579554

RESUMEN

During embryogenesis, morphogens form a concentration gradient in responsive tissue, which is then translated into a spatial cellular pattern. The mechanisms by which morphogens spread through a tissue to establish such a morphogenetic field remain elusive. Here, we investigate by mutually complementary simulations and in vivo experiments how Wnt morphogen transport by cytonemes differs from typically assumed diffusion-based transport for patterning of highly dynamic tissue such as the neural plate in zebrafish. Stochasticity strongly influences fate acquisition at the single cell level and results in fluctuating boundaries between pattern regions. Stable patterning can be achieved by sorting through concentration dependent cell migration and apoptosis, independent of the morphogen transport mechanism. We show that Wnt transport by cytonemes achieves distinct Wnt thresholds for the brain primordia earlier compared with diffusion-based transport. We conclude that a cytoneme-mediated morphogen transport together with directed cell sorting is a potentially favored mechanism to establish morphogen gradients in rapidly expanding developmental systems.


Asunto(s)
Tipificación del Cuerpo/fisiología , Regulación del Desarrollo de la Expresión Génica , Vertebrados/embriología , Proteínas Wnt/fisiología , Animales , Apoptosis , Encéfalo/embriología , Linaje de la Célula , Movimiento Celular , Biología Computacional , Simulación por Computador , Desarrollo Embrionario , Cresta Neural/embriología , Placa Neural/embriología , Transporte de Proteínas , Transducción de Señal , Programas Informáticos , Procesos Estocásticos , Pez Cebra/embriología , beta Catenina/fisiología
4.
Ibrain ; 9(3): 316-325, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37786762

RESUMEN

Alzheimer's disease (AD), recognized as the leading cause of dementia, occupies a prominent position on the list of significant neurodegenerative disorders, representing a significant global health concern with far-reaching implications at both individual and societal levels. The primary symptom of Alzheimer's disease is a decrease in synaptic potency along with synaptic connection loss. Synapses, which act as important linkages between neuronal units within the cerebral region, are critical in signal transduction processes essential to orchestrating cognitive tasks. Synaptic connections act as critical interconnections between neuronal cells inside the cerebral environment, facilitating critical signal transduction processes required for cognitive functions. The confluence of axonal and dendritic filopodial extensions culminates in the creation of intercellular connections, coordinated by various signals and molecular mechanisms. The progression of synaptic maturation and plasticity is a critical determinant in maintaining mental well-being, and abnormalities in these processes have been linked to the development of neurodegenerative diseases. Wnt signaling pathways are important to the orchestration of synapse development. This review examines the complicated interplay between Wnt signaling and dendritic filopodia, including an examination of the regulatory complexities and molecular machinations involved in synaptogenesis progression. Then, these findings are contextualized within the context of AD pathology, allowing for the consideration of prospective therapeutic approaches based on the findings and development of novel avenues for future scientific research.

5.
Cell Res ; 33(9): 661-678, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37460804

RESUMEN

Studies of cultured embryos have provided insights into human peri-implantation development. However, detailed knowledge of peri-implantation lineage development as well as underlying mechanisms remains obscure. Using 3D-cultured human embryos, herein we report a complete cell atlas of the early post-implantation lineages and decipher cellular composition and gene signatures of the epiblast and hypoblast derivatives. In addition, we develop an embryo-like assembloid (E-assembloid) by assembling naive hESCs and extraembryonic cells. Using human embryos and E-assembloids, we reveal that WNT, BMP and Nodal signaling pathways synergistically, but functionally differently, orchestrate human peri-implantation lineage development. Specially, we dissect mechanisms underlying extraembryonic mesoderm and extraembryonic endoderm specifications. Finally, an improved E-assembloid is developed to recapitulate the epiblast and hypoblast development and tissue architectures in the pre-gastrulation human embryo. Our findings provide insights into human peri-implantation development, and the E-assembloid offers a useful model to disentangle cellular behaviors and signaling interactions that drive human embryogenesis.


Asunto(s)
Embrión de Mamíferos , Estratos Germinativos , Humanos , Embrión de Mamíferos/metabolismo , Implantación del Embrión , Endodermo , Mesodermo/metabolismo , Desarrollo Embrionario
6.
Curr Opin Genet Dev ; 57: 25-30, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31404787

RESUMEN

Cell-cell communication is essential during the development of multicellular organisms. Specialized cell protrusions called cytonemes have been identified to exchange signals between cells that are vital for tissue development. Cytonemes can carry signalling components between distant cells and thus regulate the activity levels of the corresponding signalling pathways across entire tissues. This review summarizes the key findings on the formation and function of cytonemes in tissue development.


Asunto(s)
Proteínas Morfogenéticas Óseas/genética , Desarrollo Embrionario/genética , Proteínas Hedgehog/genética , Proteínas Wnt/genética , Animales , Comunicación Celular/genética , Humanos , Transporte de Proteínas/genética , Transducción de Señal/genética
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