Anne Mclaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge CB2 0SZ, UK.
Nat Commun. 2011;2:214. doi: 10.1038/ncomms1216.
A major challenge in neurobiology is to understand mechanisms underlying human neuronal diversification. Motor neurons (MNs) represent a diverse collection of neuronal subtypes, displaying differential vulnerability in different human neurodegenerative diseases. The ability to manipulate cell subtype diversification is critical to establish accurate, clinically relevant in vitro disease models. Retinoid signalling contributes to caudal precursor specification and subsequent MN subtype diversification. Here we investigate the necessity for retinoic acid in motor neurogenesis from human embryonic stem cells. We show that activin/nodal signalling inhibition, followed by sonic hedgehog agonist treatment, is sufficient for MN precursor specification, which occurs even in the presence of retinoid pathway antagonists. Importantly, precursors mature into HB9/ChAT-expressing functional MNs. Furthermore, retinoid-independent motor neurogenesis results in a ground state biased to caudal, medial motor columnar identities from which a greater retinoid-dependent diversity of MNs, including those of lateral motor columns, can be selectively derived in vitro.
神经生物学的一个主要挑战是理解人类神经元多样化的机制。运动神经元 (MNs) 代表了多种神经元亚型，在不同的人类神经退行性疾病中表现出不同的易感性。操纵细胞亚型多样化的能力对于建立准确、具有临床相关性的体外疾病模型至关重要。类视黄醇信号有助于尾部前体细胞的特化和随后的 MN 亚型多样化。在这里，我们研究了视黄酸在人胚胎干细胞运动神经发生中的必要性。我们表明，激活素/诺拉信号抑制，随后使用 sonic hedgehog 激动剂处理，足以用于 MN 前体细胞的特化，即使存在视黄酸途径拮抗剂也是如此。重要的是，前体细胞成熟为 HB9/ChAT 表达的功能性 MNs。此外，非视黄醇依赖性运动神经发生导致尾部、内侧运动柱的基础状态偏向，从中可以在体外选择性地衍生出更多的视黄醇依赖性 MN 多样性，包括外侧运动柱的 MN。
