Gamma motor neurons express distinct genetic markers at birth and require muscle spindle-derived GDNF for postnatal survival
Gamma motor neurons express distinct genetic markers at birth and require muscle spindle-derived GDNF for postnatal survival
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DOI：
10.1186/1749-8104-4-42
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发表时间：
2009-12-02
影响因子：
3.6
通讯作者：
Alvarez, Francisco J.
中科院分区：
文献类型：
--
作者：
Shneider, Neil A.;Brown, Meghan N.;Alvarez, Francisco J.
背景：γ运动神经元（gamma-MNs）选择性支配肌梭内纤维并调节其对牵拉的敏感性。它们构成了一个独特的亚群，在形态学，生理学和连接性方面与α-MN不同，α-MN支配梭外肌纤维并施加力。控制功能不同的梭运动神经元分化的机制尚不清楚。由于缺乏特异性区分和操纵γ-MN的分子标记，这一问题的进展受到限制。最近，有报道早期胚胎γ-MN前体依赖于GDNF。利用这一知识，我们的特点是遗传策略，以标记发展中的γ-MN的GDNF受体表达的基础上，表明他们的生存严格依赖于肌梭源性GDNF和产生的动物模型，其中γ-MN是选择性loss.Results：在小鼠杂合子的Hb 9：：GFP转基因和一个tau-lacZ标记（TLZ）等位基因的GDNF受体Gfr α 1，我们证明了小运动神经元与高Gfr α 1-TLZ表达和缺乏Hb 9：：GFP显示γ-MN的结构和突触特征，并且在缺乏靶肌梭的突变体中选择性丢失。肌梭的丢失也导致一些大直径MN中Gfra 1表达的下调，这表明梭衍生因子也可能影响具有β-骨骼肌梭动侧支的α-MN群体。这些分子标记可用于识别从出生到成年的γ-MN，并区分外周中的γ-和β-运动轴突。我们还发现，出生后的γ-MN也区分低表达的神经元核蛋白（NeuN）。有了这些标记的γ-MN身份，我们显示后，有条件地消除GDNF从肌梭的γ-MN的生存是选择性地依赖于纺锤体衍生的GDNF在出生后的第一个2周的发展。结论：新生儿γ-MN显示出独特的分子特征，其特征在于一系列标志物- Gfr α 1、Hb 9：：GFP和NeuN -的差异表达以及对肌梭衍生的GDNF的选择性依赖。从肌梭中缺失GDNF表达导致γ-MN的选择性消除，同时保留梭及其感觉神经支配。这提供了一个小鼠模型，探讨运动行为中的γ-fusimotor活动的具体作用。
Background: Gamma motor neurons (gamma-MNs) selectively innervate muscle spindle intrafusal fibers and regulate their sensitivity to stretch. They constitute a distinct subpopulation that differs in morphology, physiology and connectivity from alpha-MNs, which innervate extrafusal muscle fibers and exert force. The mechanisms that control the differentiation of functionally distinct fusimotor neurons are unknown. Progress on this question has been limited by the absence of molecular markers to specifically distinguish and manipulate gamma-MNs. Recently, it was reported that early embryonic gamma-MN precursors are dependent on GDNF. Using this knowledge we characterized genetic strategies to label developing gamma-MNs based on GDNF receptor expression, showed their strict dependence for survival on muscle spindle-derived GDNF and generated an animal model in which gamma-MNs are selectively lost.Results: In mice heterozygous for both the Hb9::GFP transgene and a tau-lacZ-labeled (TLZ) allele of the GDNF receptor Gfr alpha 1, we demonstrated that small motor neurons with high Gfr alpha 1-TLZ expression and lacking Hb9::GFP display structural and synaptic features of gamma-MNs and are selectively lost in mutants lacking target muscle spindles. Loss of muscle spindles also results in the downregulation of Gfra1 expression in some large diameter MNs, suggesting that spindle-derived factors may also influence populations of alpha-MNs with beta-skeletofusimotor collaterals. These molecular markers can be used to identify gamma-MNs from birth to the adult and to distinguish gamma- from beta-motor axons in the periphery. We also found that postnatal gamma-MNs are also distinguished by low expression of the neuronal nuclear protein (NeuN). With these markers of gamma-MN identity, we show after conditional elimination of GDNF from muscle spindles that the survival of gamma-MNs is selectively dependent on spindle-derived GDNF during the first 2 weeks of postnatal development. Conclusion: Neonatal gamma-MNs display a unique molecular profile characterized by the differential expression of a series of markers - Gfr alpha 1, Hb9::GFP and NeuN - and the selective dependence on muscle spindle-derived GDNF. Deletion of GDNF expression from muscle spindles results in the selective elimination of gamma-MNs with preservation of the spindle and its sensory innervation. This provides a mouse model with which to explore the specific role of gamma-fusimotor activity in motor behaviors.