Department of Biochemistry and Biophysics, Programs in Developmental Biology, Genetics, and Human Genetics, Cardiovascular Research Institute, Liver Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Dev Cell. 2010 Jun 15;18(6):973-84. doi: 10.1016/j.devcel.2010.05.009.
Extracellular matrix (ECM) remodeling is critical for organogenesis, yet its molecular regulation is poorly understood. In zebrafish, asymmetric migration of the epithelial lateral plate mesoderm (LPM) displaces the gut leftward, allowing correct placement of the liver and pancreas. To observe LPM migration at cellular resolution, we transgenically expressed EGFP under the control of the regulatory sequences of the bHLH transcription factor gene hand2. We found that laminin is distributed along the LPM/gut boundary during gut looping, and that it appears to become diminished by the migrating hand2-expressing cells. Laminin diminishment is necessary for LPM migration and is dependent on matrix metalloproteinase (MMP) activity. Loss of Hand2 function causes reduced MMP activity and prolonged laminin deposition at the LPM/gut boundary, leading to failed asymmetric LPM migration and gut looping. Our study reveals an unexpected role for Hand2, a key regulator of cell specification and differentiation, in modulating ECM remodeling during organogenesis.
细胞外基质（ECM）重塑对于器官发生至关重要，但对其分子调节知之甚少。在斑马鱼中，上皮侧板中胚层（LPM）的不对称迁移将肠道向左移位，从而使肝脏和胰腺正确定位。为了以细胞分辨率观察 LPM 迁移，我们在 bHLH 转录因子基因 hand2 的调控序列的控制下，通过转基因表达 EGFP。我们发现，层粘连蛋白在肠环曲过程中沿 LPM/肠边界分布，并且似乎被表达 hand2 的迁移细胞减少。层粘连蛋白减少对于 LPM 迁移是必需的，并且依赖于基质金属蛋白酶（MMP）活性。Hand2 功能的丧失导致 MMP 活性降低和 LPM/肠边界处层粘连蛋白沉积延长，导致不对称 LPM 迁移和肠环曲失败。我们的研究揭示了 Hand2 的一个意想不到的作用，Hand2 是细胞特化和分化的关键调节因子，在器官发生过程中调节 ECM 重塑。
