Department of Biology, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA; Department of Embryology, Carnegie Institution for Science, 3520 San Martin Drive, Baltimore, MD 21218, USA.
Department of Biology, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA; Department of Embryology, Carnegie Institution for Science, 3520 San Martin Drive, Baltimore, MD 21218, USA.
Cell Rep. 2017 Oct 31;21(5):1253-1266. doi: 10.1016/j.celrep.2017.10.031.
Skeletal muscle regeneration requires resident muscle stem cells, termed satellite cells (SCs). SCs are largely quiescent during homeostasis yet become activated upon injury to supply myonuclei and self-renewed SCs. Molecular mechanisms underlying the competence of SCs to proliferate and self-renew in response to injury remain unclear. Here, we show that CREB activity establishes proliferative potential during SC quiescence. SCs with inhibited CREB activity remain quiescent and positioned in their niche, but upon injury, they cannot enter or maintain a proliferative state for expansion and self-renewal. We demonstrate mechanistically that Mpp7 is a CREB target and its functional mediator. MPP7 loss affects the level and sub-cellular localization of AMOT and YAP1 in quiescent SCs. Furthermore, MPP7 and AMOT are required for YAP1 nuclear accumulation, and the three are individually required for a proliferative state in myoblasts. We propose that the CREB-MPP7-AMOT-YAP1 axis establishes the competence of quiescent SCs to expand and self-renew, thereby preserving stem cell function.
骨骼肌再生需要驻留的肌肉干细胞，称为卫星细胞（SCs）。在稳态下，SCs 大部分处于静止状态，但在受伤时会被激活，以提供肌核和自我更新的SCs。SCs 响应损伤增殖和自我更新的分子机制尚不清楚。在这里，我们表明 CREB 活性在 SC 静止时建立增殖潜能。抑制 CREB 活性的SCs 仍然处于静止状态，并定位于其龛位，但在受伤后，它们无法进入或维持增殖状态以进行扩张和自我更新。我们从机制上证明 Mpp7 是 CREB 的靶标和功能介质。MPP7 的缺失会影响静止 SC 中 AMOT 和 YAP1 的水平和亚细胞定位。此外，MPP7 和 AMOT 对于 YAP1 的核积累是必需的，并且它们在成肌细胞中各自对于增殖状态是必需的。我们提出，CREB-MPP7-AMOT-YAP1 轴建立了静止 SC 扩张和自我更新的能力，从而维持干细胞功能。
