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1.
iScience ; 27(3): 109247, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38439969

RESUMO

In normal intestines, a fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation profiles and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profiles, a fetal/regenerative/revival state was induced following YAP activation via a collagen type I-enriched microenvironment. Mechanistically, YAP transcription was promoted by activating AP-1 and TEAD-dependent transcription and suppressing intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying YAP regulatory elements, a potential target of CRC treatment.

2.
Neuron ; 111(1): 65-80.e6, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36334595

RESUMO

The primary cilium is a central signaling component during embryonic development. Here we focus on CROCCP2, a hominid-specific gene duplicate from ciliary rootlet coiled coil (CROCC), also known as rootletin, that encodes the major component of the ciliary rootlet. We find that CROCCP2 is highly expressed in the human fetal brain and not in other primate species. CROCCP2 gain of function in the mouse embryonic cortex and human cortical cells and organoids results in decreased ciliogenesis and increased cortical progenitor amplification, particularly basal progenitors. CROCCP2 decreases ciliary dynamics by inhibition of the IFT20 ciliary trafficking protein, which then impacts neurogenesis through increased mTOR signaling. Loss of function of CROCCP2 in human cortical cells and organoids leads to increased ciliogenesis, decreased mTOR signaling, and impaired basal progenitor amplification. These data identify CROCCP2 as a human-specific modifier of cortical neurogenesis that acts through modulation of ciliary dynamics and mTOR signaling.


Assuntos
Cílios , Transdução de Sinais , Animais , Humanos , Camundongos , Cílios/metabolismo , Citoesqueleto/metabolismo , Neurogênese , Serina-Treonina Quinases TOR/metabolismo
3.
Neuron ; 103(6): 1096-1108.e4, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31353074

RESUMO

During neurogenesis, progenitors switch from self-renewal to differentiation through the interplay of intrinsic and extrinsic cues, but how these are integrated remains poorly understood. Here, we combine whole-genome transcriptional and epigenetic analyses with in vivo functional studies to demonstrate that Bcl6, a transcriptional repressor previously reported to promote cortical neurogenesis, acts as a driver of the neurogenic transition through direct silencing of a selective repertoire of genes belonging to multiple extrinsic pathways promoting self-renewal, most strikingly the Wnt pathway. At the molecular level, Bcl6 represses its targets through Sirt1 recruitment followed by histone deacetylation. Our data identify a molecular logic by which a single cell-intrinsic factor represses multiple extrinsic pathways that favor self-renewal, thereby ensuring robustness of neuronal fate transition.


Assuntos
Autorrenovação Celular/genética , Repressão Epigenética/genética , Histonas/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Sirtuína 1/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Proteínas Hedgehog/metabolismo , Código das Histonas , Camundongos , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , RNA-Seq , Receptores Notch/metabolismo , Transdução de Sinais/genética , Via de Sinalização Wnt/genética
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