Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm, Sweden.
Development. 2011 Aug;138(16):3399-408. doi: 10.1242/dev.065482. Epub 2011 Jul 13.
The severe disorders associated with a loss or dysfunction of midbrain dopamine neurons (DNs) have intensified research aimed at deciphering developmental programs controlling midbrain development. The homeodomain proteins Lmx1a and Lmx1b are important for the specification of DNs during embryogenesis, but it is unclear to what degree they may mediate redundant or specific functions. Here, we provide evidence showing that DN progenitors in the ventral midbrain can be subdivided into molecularly distinct medial and lateral domains, and these subgroups show different sensitivity to the loss of Lmx1a and Lmx1b. Lmx1a is specifically required for converting non-neuronal floor-plate cells into neuronal DN progenitors, a process that involves the establishment of Notch signaling in ventral midline cells. On the other hand, lateral DN progenitors that do not appear to originate from the floor plate are selectively ablated in Lmx1b mutants. In addition, we also reveal an unanticipated role for Lmx1b in regulating Phox2a expression and the sequential specification of ocular motor neurons (OMNs) and red nucleus neurons (RNNs) from progenitors located lateral to DNs in the midbrain. Our data therefore establish that Lmx1b influences the differentiation of multiple neuronal subtypes in the ventral midbrain, whereas Lmx1a appears to be exclusively devoted to the differentiation of the DN lineage.
中脑多巴胺神经元 (DN) 丧失或功能障碍相关的严重疾病促使人们深入研究控制中脑发育的发育程序。同源域蛋白 Lmx1a 和 Lmx1b 对于胚胎发生过程中 DN 的特化是重要的，但它们在多大程度上可能介导冗余或特定功能尚不清楚。在这里，我们提供的证据表明，腹侧中脑的 DN 祖细胞可以细分为分子上不同的内侧和外侧区域，并且这些亚群对 Lmx1a 和 Lmx1b 的丧失表现出不同的敏感性。Lmx1a 特异性地需要将非神经元基板细胞转化为神经元 DN 祖细胞，这一过程涉及在腹中线细胞中建立 Notch 信号。另一方面，似乎不是起源于基板的外侧 DN 祖细胞在 Lmx1b 突变体中被选择性地消除。此外，我们还揭示了 Lmx1b 调节 Phox2a 表达和从中脑 DN 侧位祖细胞顺序特化眼动神经元 (OMN) 和红核神经元 (RNN) 的意想不到的作用。因此，我们的数据表明 Lmx1b 影响腹侧中脑多种神经元亚型的分化，而 Lmx1a 似乎专门用于 DN 谱系的分化。
