Abstract
The proper localization of ß-actin mRNA and protein is essential for growth cone guidance and axon elongation in cultured neurons. In addition, decreased levels of ß-actin mRNA and protein have been identified in the growth cones of motor neurons cultured from a mouse model of Spinal Muscular Atrophy (SMA), suggesting that ß-actin loss-of-function at growth cones or pre-synaptic nerve terminals could contribute to the pathogenesis of this disease. However, the role of ß-actin in motor neurons in vivo and its potential relevance to disease has yet to be examined. We therefore generated motor neuron specific ß-actin knock-out mice (Actb-MNsKO) to investigate the function of ß-actin in motor neurons in vivo. Surprisingly, ß-actin was not required for motor neuron viability or neuromuscular junction maintenance. Skeletal muscle from Actb-MNsKO mice showed no histological indication of denervation and did not significantly differ from controls in several measurements of physiologic function. Finally, motor axon regeneration was unimpaired in Actb-MNsKO mice, suggesting that ß-actin is not required for motor neuron function or regeneration in vivo.
Highlights
The cytoskeletal protein actin has well characterized roles in many aspects of neuronal development and function from growth cone dynamics to the remodeling of dendritic spines [1,2]
Spinal cord sections from control and Actb-MNsKO mice were stained for ß-actin protein and choline acetyltransferase (ChAT), a marker for motor neurons. ß-actin expression was ubiquitous throughout the spinal cord, it was relatively weak in the cell bodies of control motor neurons (Figure 1F top), consistent with previous reports indicating that ßactin is present in neuronal cell bodies only at low levels in vivo [33,34]
The dispensability of ß-actin in motor neurons in vivo was surprising given that deficits in ß-actin mRNA and protein localization correlated strongly with growth cone and axon elongation defects observed in cultured Spinal Muscular Atrophy (SMA) motor neurons [12]
Summary
The cytoskeletal protein actin has well characterized roles in many aspects of neuronal development and function from growth cone dynamics to the remodeling of dendritic spines [1,2]. SSactin is enriched at the leading edge of growth cones via an mRNA localization and local translation mechanism [4,5]. The 39-UTR of ß-actin mRNA contains a 54 nucleotide sequence called the zipcode which is bound co-transcriptionally by zipcode binding protein 1 (ZBP1, known as IMP1 in humans, mIMP or CRDBP in mice) [5,6,7,8]. ZBP1 facilitates the transport of ß-actin mRNA from the cell body to the growth cone while inhibiting its translation [5]. Attractive guidance cues received by the growth cone initiate a signaling cascade that results in the release and translation of ß-actin mRNA, thereby generating a localized increase of newly translated ß-actin which is hypothesized to be an underlying mechanism behind growth cone turning [9,10]
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