Leto Ketty, Carletti Barbara, Williams Ian Martin, Magrassi Lorenzo, Rossi Ferdinando
Department of Neuroscience and Rita Levi Montalcini Centre for Brain Repair, University of Turin, 10125 Turin, Italy.
J Neurosci. 2006 Nov 8;26(45):11682-94. doi: 10.1523/JNEUROSCI.3656-06.2006.
Different cerebellar phenotypes are generated according to a precise spatiotemporal schedule, in which projection neurons precede local interneurons. Glutamatergic neurons develop from the rhombic lip, whereas GABAergic neurons originate from the ventricular neuroepithelium. Progenitors in these germinal layers are committed toward specific phenotypes already at early ontogenetic stages. GABAergic interneurons are thought to derive from a subset of ventricular zone cells, which migrate in the white matter and proliferate up to postnatal life. During this period, different interneuron categories are produced according to an inside-out sequence, from the deep nuclei to the molecular layer (we show here that nuclear interneurons are also born during late embryonic and early postnatal days, after glutamatergic and GABAergic projection neurons). To ask whether distinct interneuron phenotypes share common precursors or derive from multiple fate-restricted progenitors, we examined the behavior of embryonic and postnatal rat cerebellar cells heterotopically/heterochronically transplanted to syngenic hosts. In all conditions, donor cells achieved a high degree of integration in the cerebellar cortex and deep nuclei and acquired GABAergic interneuron phenotypes appropriate for the host age and engraftment site. Therefore, contrary to other cerebellar types, which derive from dedicated precursors, GABAergic interneurons are produced by a common pool of progenitors, which maintain their full developmental potentialities up to late ontogenetic stages and adopt mature identities in response to local instructive cues. In this way, the numbers and types of inhibitory interneurons can be set by spatiotemporally patterned signals to match the functional requirements of developing cerebellar circuits.
不同的小脑表型是按照精确的时空计划产生的，其中投射神经元先于局部中间神经元出现。谷氨酸能神经元由菱唇发育而来，而γ-氨基丁酸能（GABAergic）神经元起源于室管膜神经上皮。这些生发层中的祖细胞在个体发育早期就已确定为特定表型。GABA能中间神经元被认为来源于室管膜区细胞的一个子集，这些细胞在白质中迁移并增殖直至出生后。在此期间，不同类别的中间神经元按照由内向外的顺序产生，从深部核团到分子层（我们在此表明，核内中间神经元也在胚胎后期和出生后早期产生，在谷氨酸能和GABA能投射神经元之后）。为了探究不同的中间神经元表型是否共享共同的前体或源自多个命运受限的祖细胞，我们检测了异位/异时移植到同基因宿主中的胚胎和出生后大鼠小脑细胞的行为。在所有情况下，供体细胞在小脑皮质和深部核团中实现了高度整合，并获得了适合宿主年龄和植入部位的GABA能中间神经元表型。因此，与源自特定前体的其他小脑类型不同，GABA能中间神经元由共同的祖细胞群体产生，这些祖细胞在个体发育后期仍保持其全部发育潜能，并根据局部诱导信号形成成熟的身份。通过这种方式，抑制性中间神经元的数量和类型可以由时空模式化的信号设定，以匹配发育中小脑回路的功能需求。
