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1.
EMBO Rep ; 25(5): 2202-2219, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38600346

RESUMO

Neural progenitor cells within the cerebral cortex undergo a characteristic switch between symmetric self-renewing cell divisions early in development and asymmetric neurogenic divisions later. Yet, the mechanisms controlling this transition remain unclear. Previous work has shown that early but not late neural progenitor cells (NPCs) endogenously express the autism-linked transcription factor Foxp1, and both loss and gain of Foxp1 function can alter NPC activity and fate choices. Here, we show that premature loss of Foxp1 upregulates transcriptional programs regulating angiogenesis, glycolysis, and cellular responses to hypoxia. These changes coincide with a premature destabilization of HIF-1α, an elevation in HIF-1α target genes, including Vegfa in NPCs, and precocious vascular network development. In vitro experiments demonstrate that stabilization of HIF-1α in Foxp1-deficient NPCs rescues the premature differentiation phenotype and restores NPC maintenance. Our data indicate that the endogenous decline in Foxp1 expression activates the HIF-1α transcriptional program leading to changes in the tissue environment adjacent to NPCs, which, in turn, might alter their self-renewal and neurogenic capacities.


Assuntos
Córtex Cerebral , Fatores de Transcrição Forkhead , Subunidade alfa do Fator 1 Induzível por Hipóxia , Células-Tronco Neurais , Proteínas Repressoras , Transdução de Sinais , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Animais , Camundongos , Córtex Cerebral/metabolismo , Córtex Cerebral/citologia , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Neovascularização Fisiológica/genética , Diferenciação Celular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Neurogênese/genética , Glicólise , Angiogênese
2.
Dev Biol ; 504: 75-85, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37708968

RESUMO

Tissue development and regeneration are dynamic processes involving complex cell migration and cell-cell interactions. We have developed a protocol for complementary time-lapse and three-dimensional (3D) imaging of tissue for developmental and regeneration studies which we apply here to the zebrafish cardiac vasculature. 3D imaging of fixed specimens is used to first define the subject at high resolution then live imaging captures how it changes dynamically. Hearts from adult and juvenile zebrafish are extracted and cleaned in preparation for the different imaging modalities. For whole-mount 3D confocal imaging, single or multiple hearts with native fluorescence or immuno-labeling are prepared for stabilization or clearing, and then imaged. For live imaging, hearts are placed in a prefabricated fluidic device and set on a temperature-controlled microscope for culture and imaging over several days. This protocol allows complete visualization of morphogenic processes in a 3D context and provides the ability to follow cell behaviors to complement in vivo and fixed tissue studies. This culture and imaging protocol can be applied to different cell and tissue types. Here, we have used it to observe zebrafish coronary vasculature and the migration of coronary endothelial cells during heart regeneration.


Assuntos
Células Endoteliais , Peixe-Zebra , Animais , Células Endoteliais/metabolismo , Coração/diagnóstico por imagem , Imageamento Tridimensional/métodos
3.
Elife ; 82019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31702553

RESUMO

The cardiac lymphatic vascular system and its potentially critical functions in heart patients have been largely underappreciated, in part due to a lack of experimentally accessible systems. We here demonstrate that cardiac lymphatic vessels develop in young adult zebrafish, using coronary arteries to guide their expansion down the ventricle. Mechanistically, we show that in cxcr4a mutants with defective coronary artery development, cardiac lymphatic vessels fail to expand onto the ventricle. In regenerating adult zebrafish hearts the lymphatic vasculature undergoes extensive lymphangiogenesis in response to a cryoinjury. A significant defect in reducing the scar size after cryoinjury is observed in zebrafish with impaired Vegfc/Vegfr3 signaling that fail to develop intact cardiac lymphatic vessels. These results suggest that the cardiac lymphatic system can influence the regenerative potential of the myocardium.


Assuntos
Coração/fisiologia , Linfangiogênese/fisiologia , Vasos Linfáticos/fisiopatologia , Miocárdio/metabolismo , Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados , Vasos Coronários/metabolismo , Vasos Coronários/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Coração/crescimento & desenvolvimento , Humanos , Linfangiogênese/genética , Vasos Linfáticos/lesões , Vasos Linfáticos/metabolismo , Mutação , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Regeneração/genética , Regeneração/fisiologia , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
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