p75NTR prevents the onset of cerebellar granule cell migration via RhoA activation.
p75NTR prevents the onset of cerebellar granule cell migration via RhoA activation.
复制标题
DOI：
10.7554/elife.79934
复制
发表时间：
2022-08-30
期刊：
影响因子：
7.7
通讯作者：
Friedman, Wilma J.
中科院分区：
文献类型：
--
作者：
Zanin, Juan P.;Friedman, Wilma J.
神经元迁移是脑发育的基本过程之一。一些神经发育障碍可以追溯到失调的迁移。虽然大量的努力已经被放置在识别刺激迁移的分子信号，很少有人知道的潜在机制，限制迁移。这些限制性机制对于正常发育至关重要，因为它有助于协调每个神经元群体到达并建立正确连接的时间。此外，防止迁移远离增殖龛是必要的，以维持一个池的增殖细胞，直到达到适当数量的神经元祖细胞。在这里，使用小鼠和大鼠，我们确定了一个抗迁移作用的p75神经营养因子受体（p75 NTR）在小脑发育。我们的研究结果表明，颗粒细胞前体（GCPs）强烈表达p75 NTR的外部颗粒层（EGL），当他们在出生后的发展过程中增殖，但是，他们不表达p75 NTR时，无论是从菱形唇在胚胎发育过程中或从EGL在出生后的发展。我们发现，p75 NTR通过维持活性RhoA水平的升高来防止GCP迁移。p75 NTR的表达足以防止颗粒细胞的迁移，即使在BDNF（脑源性神经营养因子）的存在下，这是一个很好的建立的趋化信号，为这个细胞群。我们的研究结果表明，p75 NTR的表达可能是一个关键的信号，停止和维持在EGL的增殖龛中的GCPs，通过促进小脑颗粒神经元的克隆扩张。人类大脑包含数十亿个神经元，它们形成巨大的网络，将信息传递到大脑周围和身体的其他部位。神经元的数量和位置以及它们之间的连接会影响大脑的工作方式，因此身体会仔细控制神经元的形成方式、位置和时间。大脑中的大多数神经元在我们出生之前就从称为神经元前体的支持细胞群中产生了。通常，这些细胞必须从一个地方迁移到另一个地方，以使神经元处于校正位置。例如，在胚胎大脑的一个区域，称为菱形唇，神经元前体产生颗粒细胞-一种在小脑中发现的神经元，小脑是成人大脑的一个区域，控制我们的移动能力。在制造神经元之前，前体细胞首先必须从菱形唇迁移到邻近区域。先前的研究表明，一种名为p75 NTR的蛋白质可能有助于控制脑细胞的迁移能力，但其确切作用仍不清楚。为了解决这个问题，Zanin和Friedman研究了p75 NTR在小鼠和大鼠颗粒细胞前体迁移中的作用。实验发现，在缺乏这种蛋白质的动物中，颗粒细胞前体细胞比正常动物更早开始迁移出菱形唇，导致成年小脑中颗粒细胞数量过多，这会影响动物的正常发育。p75 NTR蛋白似乎通过激活另一种称为RhoA的蛋白质来阻止细胞迁移。了解身体如何控制神经元前体和其他脑细胞迁移，有助于我们了解健康个体和某些神经系统疾病（包括自闭症）的大脑发育。下一步是确定p75 NTR是否在人类大脑中也起着类似的作用。
Neuronal migration is one of the fundamental processes during brain development. Several neurodevelopmental disorders can be traced back to dysregulated migration. Although substantial efforts have been placed in identifying molecular signals that stimulate migration, little is known about potential mechanisms that restrict migration. These restrictive mechanisms are essential for proper development since it helps coordinate the timing for each neuronal population to arrive and establish proper connections. Moreover, preventing migration away from a proliferative niche is necessary in maintaining a pool of proliferating cells until the proper number of neuronal progenitors is attained. Here, using mice and rats, we identify an anti-migratory role for the p75 neurotrophin receptor (p75NTR) in cerebellar development. Our results show that granule cell precursors (GCPs) robustly express p75NTR in the external granule layer (EGL) when they are proliferating during postnatal development, however, they do not express p75NTR when they migrate either from the rhombic lip during embryonic development or from the EGL during postnatal development. We show that p75NTR prevented GCP migration by maintaining elevated levels of active RhoA. The expression of p75NTR was sufficient to prevent the migration of the granule cells even in the presence of BDNF (brain-derived neurotrophic factor), a well-established chemotactic signal for this cell population. Our findings suggest that the expression of p75NTR might be a critical signal that stops and maintains the GCPs in the proliferative niche of the EGL, by promoting the clonal expansion of cerebellar granule neurons. The human brain contains billions of neurons that form vast networks to relay information around the brain and to the rest of the body. The numbers and locations of neurons, and the connections between them, affect how the brain works, so the body carefully controls how, where and when neurons form. Most of the neurons in the brain arise before we are born from groups of supporting cells known as neuronal precursors. Often, these cells must migrate from one place to another to make neurons in the correction location. For example, neuronal precursors in an area of the embryo brain, called the rhombic lip, produce granule cells – a type of neuron found in the cerebellum, a region of the adult brain that controls our ability to move around. Before making the neurons, the precursor cells first have to migrate out of the rhombic lip into a neighboring area. Previous studies indicate that a protein known as p75NTR may help to control the ability of brain cells to migrate, but its precise role remained unclear. To address this question, Zanin and Friedman investigated the role of p75NTR in the migration of granule cell precursors in mice and rats. The experiments found that in animals lacking this protein, the granule cell precursors began to migrate out of the rhombic lip earlier than in normal animals, resulting in excessive numbers of granule cells in the adult cerebellum, which can affect the normal development of an animal. The p75NTR protein appeared to prevent the cells from migrating by activating another protein called RhoA. Understanding how the body controls when neuronal precursors and other brain cells migrate helps us to understand how the brain develops in healthy individuals and certain neurological disorders, including autism. The next step is to find out whether p75NTR also plays a similar role in the human brain.