Hao le Thi, Duy Phan Q, An Min, Talbot Jared, Iyer Chitra C, Wolman Marc, Beattie Christine E
Wexner Medical Center Department of Neuroscience.
Department of Biochemistry and Pharmacology, and.
J Neurosci. 2017 Nov 29;37(48):11559-11571. doi: 10.1523/JNEUROSCI.1528-17.2017. Epub 2017 Oct 23.
Motoneurons establish a critical link between the CNS and muscles. If motoneurons do not develop correctly, they cannot form the required connections, resulting in movement defects or paralysis. Compromised development can also lead to degeneration because the motoneuron is not set up to function properly. Little is known, however, regarding the mechanisms that control vertebrate motoneuron development, particularly the later stages of axon branch and dendrite formation. The motoneuron disease spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein leading to defects in vertebrate motoneuron development and synapse formation. Here we show using zebrafish as a model system that SMN interacts with the RNA binding protein (RBP) HuD in motoneurons during formation of axonal branches and dendrites. To determine the function of HuD in motoneurons, we generated zebrafish mutants and found that they exhibited decreased motor axon branches, dramatically fewer dendrites, and movement defects. These same phenotypes are present in animals expressing low levels of SMN, indicating that both proteins function in motoneuron development. HuD binds and transports mRNAs and one of its target mRNAs, , is involved in axonal outgrowth. We found that was decreased in both and mutants. Importantly, transgenic expression of HuD in motoneurons of mutants rescued the motoneuron defects, the movement defects, and mRNA levels. These data support that the interaction between SMN and HuD is critical for motoneuron development and point to a role for RBPs in SMA. In zebrafish models of the motoneuron disease spinal muscular atrophy (SMA), motor axons fail to form the normal extent of axonal branches and dendrites leading to decreased motor function. SMA is caused by low levels of the survival motor neuron (SMN) protein. We show in motoneurons that SMN interacts with the RNA binding protein, HuD. Novel mutants reveal that HuD is also necessary for motor axonal branch and dendrite formation. Data also revealed that both SMN and HuD affect levels of an mRNA involved in axonal growth. Moreover, expressing HuD in SMN-deficient motoneurons can rescue the motoneuron development and motor defects caused by low levels of SMN. These data support that SMN:HuD complexes are essential for normal motoneuron development and indicate that mRNA handling is a critical component of SMA.
运动神经元在中枢神经系统和肌肉之间建立了关键联系。如果运动神经元发育不正确，它们就无法形成所需的连接，从而导致运动缺陷或瘫痪。发育受损还可能导致退化，因为运动神经元没有建立起正常功能。然而，对于控制脊椎动物运动神经元发育的机制，尤其是轴突分支和树突形成的后期阶段，人们了解甚少。运动神经元疾病脊髓性肌萎缩症（SMA）是由存活运动神经元（SMN）蛋白水平低下导致脊椎动物运动神经元发育和突触形成缺陷引起的。在这里，我们以斑马鱼为模型系统表明，在轴突分支和树突形成过程中，SMN在运动神经元中与RNA结合蛋白（RBP）HuD相互作用。为了确定HuD在运动神经元中的功能，我们生成了斑马鱼突变体，发现它们表现出运动轴突分支减少、树突数量显著减少以及运动缺陷。这些相同的表型也出现在表达低水平SMN的动物中，表明这两种蛋白在运动神经元发育中发挥作用。HuD结合并转运mRNA，其靶mRNA之一参与轴突生长。我们发现该mRNA在突变体和突变体中均减少。重要的是，在突变体的运动神经元中过表达HuD挽救了运动神经元缺陷、运动缺陷以及mRNA水平。这些数据支持SMN和HuD之间的相互作用对运动神经元发育至关重要，并表明RBP在SMA中起作用。在运动神经元疾病脊髓性肌萎缩症（SMA）的斑马鱼模型中，运动轴突无法形成正常范围的松果体分支和树突，导致运动功能下降。SMA是由存活运动神经元（SMN）蛋白水平低下引起的。我们在运动神经元中表明SMN与RNA结合蛋白HuD相互作用。新的突变体表明HuD对运动轴突分支和树突形成也很必要。数据还显示，SMN和HuD都会影响参与轴突生长的mRNA水平。此外，在缺乏SMN的运动神经元中表达HuD可以挽救由低水平SMN引起的运动神经元发育和运动缺陷。这些数据支持SMN：HuD复合物对正常运动神经元发育至关重要，并表明mRNA处理是SMA的关键组成部分。
