Transforming growth factor-beta(s) are essential for the development of midbrain dopaminergic neurons in vitro and in vivo.
Transforming growth factor-beta(s) are essential for the development of midbrain dopaminergic neurons in vitro and in vivo.
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发表时间：
2003
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通讯作者：
L. Farkas;N. Dünker;E. Roussa;K. Unsicker;K. Krieglstein
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作者：
L. Farkas;N. Dünker;E. Roussa;K. Unsicker;K. Krieglstein
已知中脑多巴胺能神经元的发育依赖于来自腹侧中线的诱导信号，包括Sonic hedgehog（Shh）作为鉴定的分子之一。在这里，我们表明，除了嘘，转化生长因子（TGF）-β是必需的腹侧位于中脑多巴胺能神经元的诱导和生存。像Shh一样，TGF-β在早期胚胎结构中表达，如脊索和底板，以及中脑多巴胺能神经元发育的区域。从大鼠胚胎第12天（E）中脑底分离的细胞与TGF-β的治疗显着增加的酪氨酸羟化酶（TH）阳性多巴胺能神经元的数量在24小时内。TGF-β在体外中和完全取消多巴胺能神经元的诱导。在没有TGF-β的情况下，Shh不能诱导TH阳性神经元，反之亦然，中和内源性Shh消除了TGF-β在体外诱导多巴胺能神经元的能力。此外，在鸡E2-7，而不是E4-7期间，体内TGF-β的中和导致腹侧中脑底TH阳性神经元的显着减少，但在蓝斑或间脑，这表明TGF-β是必需的诱导中脑多巴胺能神经元的关键时间段在E2/E3。此外，在E6和10之间，即中脑多巴胺能神经元成熟期间不需要进一步诱导线索的时间段，TGF-β的中和也导致多巴胺能神经元的显著损失，这表明TGF-β也是促进腹侧中脑多巴胺能神经元存活所需的。总之，我们的研究结果确定TGF-β作为一个必不可少的介质诱导和维持中脑多巴胺能神经元。
Development of midbrain dopaminergic neurons is known to depend on inductive signals derived from the ventral midline, including Sonic hedgehog (Shh) as one of the identified molecules. Here we show that in addition to Shh, transforming growth factor (TGF)-beta is required for both induction and survival of ventrally located midbrain dopaminergic neurons. Like Shh, TGF-beta is expressed in early embryonic structures such as notochord and floor plate, as well as in the area where midbrain dopaminergic neurons are developing. Treatment of cells dissociated from the rat embryonic day (E) 12 midbrain floor with TGF-beta significantly increases the number of tyrosine hydroxylase (TH)-positive dopaminergic neurons within 24 hr. Neutralization of TGF-beta in vitro completely abolishes the induction of dopaminergic neurons. In the absence of TGF-beta, Shh cannot induce TH-positive neurons, and vice versa, neutralizing endogenous Shh abolishes the capacity of TGF-beta to induce dopaminergic neurons in vitro. Furthermore, neutralization of TGF-beta in vivo during chick E2-7 but not E4-7 resulted in a significant reduction in TH-positive neurons in the ventral midbrain floor but not in the locus coeruleus or diencephalon, which suggests that the TGF-beta is required for the induction of mesencephalic dopaminergic neurons with a critical time period at E2/E3. Furthermore, neutralization of TGF-beta between E6 and 10, a time period during maturation of mesencephalic dopaminergic neurons when no further inductive cues are required, also resulted in a significant loss of dopaminergic neurons, suggesting that TGF-beta is required for the promotion of survival of ventral midbrain dopaminergic neurons as well. Together, our results identify TGF-beta as an essential mediator for the induction and maintenance of midbrain dopaminergic neurons.