USP7 controls NGN3 stability and pancreatic endocrine lineage development.
USP7 controls NGN3 stability and pancreatic endocrine lineage development.
复制标题
DOI：
10.1038/s41467-023-38146-9
复制
发表时间：
2023-04-28
影响因子：
16.6
通讯作者：
Sancho, Rocio
中科院分区：
文献类型：
--
作者：
Manea, Teodora;Nelson, Jessica Kristine;Garrone, Cristina Maria;Hansson, Karin;Evans, Ian;Behrens, Axel;Sancho, Rocio
了解β细胞发育中涉及的因素和机制将指导治疗工作，以产生糖尿病的全功能β细胞。神经生成素3（NGN 3）是标记内分泌祖细胞并驱动β细胞分化的关键转录因子。在这里，我们筛选NGN 3的结合伙伴，并确定去泛素化酶USP 7作为NGN 3稳定性的关键调节因子。在机制上，USP 7与NGN 3相互作用、去泛素化并稳定NGN 3。在体内，小鼠胚胎胰腺中Usp 7的条件性敲除导致成年小鼠中胰岛形成和高血糖症的显著减少，这是由于胰腺发育期间受损的NGN 3介导的内分泌特化。此外，在β-细胞分化的人iPSC模型中内分泌特化期间USP 7的药理学抑制降低了表达NGN 3的祖细胞数量并损害β细胞分化。因此，USP 7-NGN 3轴是驱动内分泌发育和β细胞分化的重要机制，可以在治疗上加以利用。严格控制的NGN 3表达对于发育中的胰腺中的内分泌细胞生成是必不可少的，其中失调导致小鼠中的高血糖症。在这里，他们确定USP 7是NGN 3稳定性的关键翻译后调节因子，并表明该轴是内分泌发育和β细胞分化所必需的。
Understanding the factors and mechanisms involved in beta-cell development will guide therapeutic efforts to generate fully functional beta cells for diabetes. Neurogenin 3 (NGN3) is the key transcription factor that marks endocrine progenitors and drives beta-cell differentiation. Here we screen for binding partners of NGN3 and identify the deubiquitylating enzyme USP7 as a key regulator of NGN3 stability. Mechanistically, USP7 interacts with, deubiquitinates and stabilizes NGN3. In vivo, conditional knockout of Usp7 in the mouse embryonic pancreas causes a dramatic reduction in islet formation and hyperglycemia in adult mice, due to impaired NGN3-mediated endocrine specification during pancreatic development. Furthermore, pharmacological inhibition of USP7 during endocrine specification in human iPSC models of beta-cell differentiation decreases NGN3 expressing progenitor cell numbers and impairs beta cell differentiation. Thus, the USP7-NGN3 axis is an essential mechanism for driving endocrine development and beta-cell differentiation, which can be therapeutically exploited. Tightly controlled NGN3 expression is essential for endocrine cell generation in the developing pancreas, with dysregulation leading to hyperglycemia in mice. Here they identify USP7 as a key post-translational regulator of NGN3 stability and show that this axis is required for endocrine development and beta-cell differentiation.
登录
查看更多内容
影响因子：
23.9
作者：
Gribben C;Lambert C;Messal HA;Hubber EL;Rackham C;Evans I;Heimberg H;Jones P;Sancho R;Behrens A
通讯作者：
Behrens A
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
5.8
作者：
Arosio, M;Ronchi, CL;Peracchi, M
通讯作者：
Peracchi, M
影响因子：
8.2
作者：
Yang, Y.;Chang, B. H-J.;Yechoor, V.;Chen, W.;Li, L.;Tsai, M. -J.;Chan, L.
通讯作者：
Chan, L.
影响因子：
64.8
作者：
Apelqvist, Å;Li, H;Edlund, H
通讯作者：
Edlund, H