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1.
Elife ; 132024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38722021

RESUMEN

Neural stem cells (NSCs) are multipotent and correct fate determination is crucial to guarantee brain formation and homeostasis. How NSCs are instructed to generate neuronal or glial progeny is not well understood. Here, we addressed how murine adult hippocampal NSC fate is regulated and described how scaffold attachment factor B (SAFB) blocks oligodendrocyte production to enable neuron generation. We found that SAFB prevents NSC expression of the transcription factor nuclear factor I/B (NFIB) by binding to sequences in the Nfib mRNA and enhancing Drosha-dependent cleavage of the transcripts. We show that increasing SAFB expression prevents oligodendrocyte production by multipotent adult NSCs, and conditional deletion of Safb increases NFIB expression and oligodendrocyte formation in the adult hippocampus. Our results provide novel insights into a mechanism that controls Drosha functions for selective regulation of NSC fate by modulating the post-transcriptional destabilization of Nfib mRNA in a lineage-specific manner.


Asunto(s)
Hipocampo , Factores de Transcripción NFI , Células-Madre Neurales , Proteínas Asociadas a Matriz Nuclear , ARN Mensajero , Animales , Ratones , Diferenciación Celular , Hipocampo/metabolismo , Hipocampo/citología , Células-Madre Neurales/metabolismo , Factores de Transcripción NFI/metabolismo , Factores de Transcripción NFI/genética , Proteínas Asociadas a Matriz Nuclear/metabolismo , Oligodendroglía/metabolismo , Ribonucleasa III/metabolismo , Ribonucleasa III/genética , Estabilidad del ARN , ARN Mensajero/metabolismo , ARN Mensajero/genética
2.
Cell Stem Cell ; 28(10): 1822-1837.e10, 2021 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-34129813

RESUMEN

AXIN2 and LGR5 mark intestinal stem cells (ISCs) that require WNT/ß-Catenin signaling for constant homeostatic proliferation. In contrast, AXIN2/LGR5+ pericentral hepatocytes show low proliferation rates despite a WNT/ß-Catenin activity gradient required for metabolic liver zonation. The mechanisms restricting proliferation in AXIN2+ hepatocytes and metabolic gene expression in AXIN2+ ISCs remained elusive. We now show that restricted chromatin accessibility in ISCs prevents the expression of ß-Catenin-regulated metabolic enzymes, whereas fine-tuning of WNT/ß-Catenin activity by ZNRF3 and RNF43 restricts proliferation in chromatin-permissive AXIN2+ hepatocytes, while preserving metabolic function. ZNRF3 deletion promotes hepatocyte proliferation, which in turn becomes limited by RNF43 upregulation. Concomitant deletion of RNF43 in ZNRF3 mutant mice results in metabolic reprogramming of periportal hepatocytes and induces clonal expansion in a subset of hepatocytes, ultimately promoting liver tumors. Together, ZNRF3 and RNF43 cooperate to safeguard liver homeostasis by spatially and temporally restricting WNT/ß-Catenin activity, balancing metabolic function and hepatocyte proliferation.


Asunto(s)
Hígado , Ubiquitina-Proteína Ligasas/genética , Animales , Proliferación Celular , Hepatocitos/metabolismo , Hígado/crecimiento & desarrollo , Hígado/metabolismo , Ratones , Células Madre/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismo
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