Department of Neuroanatomy, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
Neural Dev. 2012 Jan 20;7:4. doi: 10.1186/1749-8104-7-4.
The hypothalamus is a brain region with essential functions for homeostasis and energy metabolism, and alterations of its development can contribute to pathological conditions in the adult, like hypertension, diabetes or obesity. However, due to the anatomical complexity of the hypothalamus, its development is not well understood. Sonic hedgehog (Shh) is a key developmental regulator gene expressed in a dynamic pattern in hypothalamic progenitor cells. To obtain insight into hypothalamic organization, we used genetic inducible fate mapping (GIFM) to map the lineages derived from Shh-expressing progenitor domains onto the four rostrocaudally arranged hypothalamic regions: preoptic, anterior, tuberal and mammillary.
Shh-expressing progenitors labeled at an early stage (before embryonic day (E)9.5) contribute neurons and astrocytes to a large caudal area including the mammillary and posterior tuberal regions as well as tanycytes (specialized median eminence glia). Progenitors labeled at later stages (after E9.5) give rise to neurons and astrocytes of the entire tuberal region and in particular the ventromedial nucleus, but not to cells in the mammillary region and median eminence. At this stage, an additional Shh-expressing domain appears in the preoptic area and contributes mostly astrocytes to the hypothalamus. Shh-expressing progenitors do not contribute to the anterior region at any stage. Finally, we show a gradual shift from neurogenesis to gliogenesis, so that progenitors expressing Shh after E12.5 generate almost exclusively hypothalamic astrocytes.
We define a fate map of the hypothalamus, based on the dynamic expression of Shh in the hypothalamic progenitor zones. We provide evidence that the large neurogenic Shh-expressing progenitor domains of the ventral diencephalon are continuous with those of the midbrain. We demonstrate that the four classical transverse zones of the hypothalamus have clearly defined progenitor domains and that there is little or no cell mixing between the tuberal and anterior or the preoptic and anterior hypothalamus. Finally, we show that, in the tuberal hypothalamus, neurons destined for every mediolateral level are produced during a period of days, in conflict with the current 'three-wave' model of hypothalamic neurogenesis. Our work sets the stage for a deeper developmental analysis of this complex and important brain region.
下丘脑是一个对维持体内平衡和能量代谢具有重要功能的脑区，其发育的改变可能导致成年后的病理状态，如高血压、糖尿病或肥胖。然而，由于下丘脑的解剖结构复杂，其发育过程尚不清楚。Sonic hedgehog（Shh）是一种关键的发育调节基因，在下丘脑祖细胞中呈动态表达模式。为了深入了解下丘脑的组织，我们使用遗传诱导命运图谱（GIFM）将源自 Shh 表达祖细胞区域的谱系映射到四个头尾排列的下丘脑区域：视前区、前区、结节区和乳头体区。
在早期（胚胎第 9.5 天之前）标记的 Shh 表达祖细胞将神经元和星形胶质细胞贡献给一个大的尾部区域，包括乳头体和后部结节区以及室管膜细胞（专门的正中隆起胶质）。在晚期（E9.5 之后）标记的祖细胞产生整个结节区的神经元和星形胶质细胞，特别是腹内侧核，但不产生乳头体区和正中隆起的细胞。在这个阶段，一个额外的 Shh 表达区域出现在视前区，并主要将星形胶质细胞贡献给下丘脑。在任何阶段，Shh 表达祖细胞都不向前区贡献。最后，我们显示了从神经发生到神经胶质发生的逐渐转变，因此在 E12.5 之后表达 Shh 的祖细胞几乎只产生下丘脑星形胶质细胞。
我们基于下丘脑祖细胞中 Shh 的动态表达，定义了下丘脑的命运图谱。我们提供的证据表明，腹侧神经胚层的大型神经生成 Shh 表达祖细胞区域与中脑的祖细胞区域连续。我们证明，下丘脑的四个经典横断区域有明确的祖细胞区域，结节区和前区或视前区和前区之间很少或没有细胞混合。最后，我们表明，在结节状下丘脑，每个中侧水平的神经元都是在几天的时间内产生的，这与当前的下丘脑神经发生“三波”模型相矛盾。我们的工作为这个复杂而重要的脑区的深入发育分析奠定了基础。
