Hagedorn L, Floris J, Suter U, Sommer L
Institute of Cell Biology, Swiss Federal Institute of Technology, ETH-Hönggerberg, Zurich, CH-8093, Switzerland.
Dev Biol. 2000 Dec 1;228(1):57-72. doi: 10.1006/dbio.2000.9936.
The question of how appropriate cell types are generated in correct numbers during development of the peripheral nervous system has become particularly intriguing with the identification of multipotent progenitor cells in postmigratory targets of the neural crest. Recently, we have provided evidence that community effects in response to factors of the TGFbeta family might represent a mechanism to suppress inappropriate nonneural fates from multipotent progenitors in developing peripheral ganglia. In culture, BMP2 and TGFbeta promote neurogenesis at the expense of a smooth-muscle-like fate in clusters of neural-crest-derived multipotent progenitor cells. We now show that the neurons generated by TGFbeta factors belong to the autonomic lineage and that cells within the developing sympathetic ganglia express TGFbeta-type II receptor. In addition to its neurogenic activity, TGFbeta but not BMP2 also induces apoptosis as an alternative fate in cultured progenitor communities. Interestingly, these fate decisions are controlled by graded changes in TGFbeta concentrations: lower doses of TGFbeta promote neurogenesis while slightly higher doses induce predominantly apoptosis. These effects of TGFbeta are specific for an early developmental stage since progenitor cells lose their competence to respond to the proapoptotic activity of TGFbeta upon neuronal differentiation. In vivo, the expression of TGFbeta3 in differentiated neurons suggests that the signal concentration gradually increases with the number of neurons formed in the autonomic ganglia. We propose that TGFbeta functions in a biphasic manner during autonomic gangliogenesis to control both neurogenesis and subsequently the number of neurons generated from progenitor cells.
随着神经嵴迁移后靶标中多能祖细胞的鉴定，在周围神经系统发育过程中如何以正确数量产生合适的细胞类型这一问题变得格外引人关注。最近，我们提供了证据表明，对TGFβ家族因子的群体效应可能代表一种机制，用于抑制发育中的外周神经节中多能祖细胞产生不适当的非神经命运。在培养中，BMP2和TGFβ以牺牲神经嵴来源的多能祖细胞簇中平滑肌样命运为代价促进神经发生。我们现在表明，TGFβ因子产生的神经元属于自主神经谱系，并且发育中的交感神经节内的细胞表达TGFβ II型受体。除了其神经发生活性外，TGFβ而非BMP2还诱导凋亡，作为培养的祖细胞群体中的另一种命运。有趣的是，这些命运决定受TGFβ浓度的梯度变化控制：较低剂量的TGFβ促进神经发生，而略高剂量则主要诱导凋亡。TGFβ的这些作用在早期发育阶段是特异性的，因为祖细胞在神经元分化后失去了对TGFβ促凋亡活性作出反应的能力。在体内，TGFβ3在分化神经元中的表达表明信号浓度随着自主神经节中形成的神经元数量逐渐增加。我们提出，TGFβ在自主神经节形成过程中以双相方式发挥作用，以控制神经发生以及随后从祖细胞产生的神经元数量。
