Differential timing of granule cell production during cerebellum development underlies generation of the foliation pattern
Differential timing of granule cell production during cerebellum development underlies generation of the foliation pattern
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DOI：
10.1186/s13064-016-0072-z
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发表时间：
2016-09-08
影响因子：
3.6
通讯作者：
Joyner, Alexandra L.
中科院分区：
文献类型：
--
作者：
Legue, Emilie;Gottshall, Jackie L.;Joyner, Alexandra L.
背景：小鼠小脑 (Cb) 具有非常复杂的叶状三维 (3D) 结构，但具有刻板的细胞结构和局部电路。人们对发育过程中决定叶状结构的细胞行为和基因知之甚少。在前后轴上，哺乳动物小脑被大小不同的小叶分开，并且沿中间外侧轴的叶状图案不同，限定了内侧蚓部和两个外侧半球。在蚓部，小叶根据遗传标准进一步分为四个前后区（前区、中央区、后区和结节区），每个区都有不同的小叶。由于每个小脑传入群投射到特定的小叶和区域，因此了解 Cb 的 3D 结构是如何获得的至关重要。在小脑发育过程中，叶状细胞需要产生颗粒细胞（gcs），颗粒细胞是大脑中数量最多的细胞类型。我们假设发育过程中四个小叶中 gc 积累的时间不同，并导致不同的小叶形态。方法和结果：为了验证这一想法，我们使用遗传诱导命运图谱来量化小鼠出生后前两周每个小叶中 gc 的积累。发现每个小叶产生GC的时间是特定的，并且相对于其他区域，中央区域小叶的GC产生时间延迟。对代表不同区域的小叶中三个时间点的 gc 增殖和分化进行量化，揭示了延迟涉及中央区域 gc 祖细胞最大分化的较晚开始和延长的增殖。在 Engrailed 突变体（En1（-/+）；En2（-/-））中进行的类似实验表明，GC 产生、增殖和分化发生了改变，与野生型小鼠相比，GC 产生、增殖和分化发生了改变，从而减弱了区域之间的差异。结论：我们的结果表明，GC 产生在小脑蚓部的每个区域中受到差异性调节，我们的突变体分析表明，GC 产生的动态变化在确定 Cb 的 3D 结构中发挥作用。
Background: The mouse cerebellum (Cb) has a remarkably complex foliated three-dimensional (3D) structure, but a stereotypical cytoarchitecture and local circuitry. Little is known of the cellular behaviors and genes that function during development to determine the foliation pattern. In the anteroposterior axis the mammalian cerebellum is divided by lobules with distinct sizes, and the foliation pattern differs along the mediolateral axis defining a medial vermis and two lateral hemispheres. In the vermis, lobules are further grouped into four anteroposterior zones (anterior, central, posterior and nodular zones) based on genetic criteria, and each has distinct lobules. Since each cerebellar afferent group projects to particular lobules and zones, it is critical to understand how the 3D structure of the Cb is acquired. During cerebellar development, the production of granule cells (gcs), the most numerous cell type in the brain, is required for foliation. We hypothesized that the timing of gc accumulation is different in the four vermal zones during development and contributes to the distinct lobule morphologies.Methods and Results: In order to test this idea, we used genetic inducible fate mapping to quantify accumulation of gcs in each lobule during the first two postnatal weeks in mice. The timing of gc production was found to be particular to each lobule, and delayed in the central zone lobules relative to the other zones. Quantification of gc proliferation and differentiation at three time-points in lobules representing different zones, revealed the delay involves a later onset of maximum differentiation and prolonged proliferation of gc progenitors in the central zone. Similar experiments in Engrailed mutants (En1(-/+); En2(-/-)), which have a smaller Cb and altered foliation pattern preferentially outside the central zone, showed that gc production, proliferation and differentiation are altered such that the differences between zones are attenuated compared to wild-type mice.Conclusions: Our results reveal that gc production is differentially regulated in each zone of the cerebellar vermis, and our mutant analysis indicates that the dynamics of gc production plays a role in determining the 3D structure of the Cb.