HDACs in Synaptic Gene Expression

The NMJ is a specialized synapse between the motor neuron and myofiber. As the motor axon nears the myofiber, it divides into multiple terminal boutons where vesicles filled with neurotransmitter acetylcholine (ACh) are released upon firing of the motor neuron. Across the synaptic cleft, the myofiber increases its surface area by developing elaborate junctional folds with a high concentration of acetylcholine receptors (AChRs). This spatial concentration of AChRs at the NMJ but not other surface areas of the myofiber is key to efficient neural-muscular communication. The expression of AChRs in skeletal muscle is strictly controlled by neural activity. In normally innervated muscle, transcription of AChR and other synaptic genes is actively repressed in all nuclei but those directly underlying the NMJs (subsynaptic nuclei). Spatially restricted expression of AChR contributes to its concentration at the NMJ. This spatially restricted expression is rapidly reversed upon loss of neural input by denervation, resulting in robust induction of AChR and other synaptic genes throughout the muscle by myogenin transcription factor. The signaling cascade that leads to synaptic gene re-expression in denervated muscle is controlled by HDAC4 (Cohen et al. 2007). Upon denervation, the induction of HDAC4 represses the transcription of Dachschund-related transcriptional corepressor 2 (Dach2), an inhibitor of myogenin transcription (Tang and Goldman 2006). Consequently, denervation induces myogenin transcription, which in turn activates synaptic genes. The activity-responsive HDAC4-Dach2-myogenin axis therefore plays a critical role in regulating the transcription of synaptic genes in response to differential neural inputs. It should be noted that siRNA analysis showed that

HDAC4 plays a more dominant role than HDAC5 in the regulation of synaptic gene transcription (Cohen et al. 2007).

The HDAC9 isoform, MITR, has also been linked to synaptic gene expression (Mejat et al. 2005). MITR was initially identified as MEF2-interacting transcriptional repressor (Sparrow et al. 1999). It turns out to be a N-terminus splice variant of HDAC9 lacking the C-terminus deacetylase domain. This finding provides the first evidence that the deacetylase domain of class IIa HDACs is not required for repressing MEF2 activity. Although both MITR and HDAC4 act as potent MEF2 repressors, MITR seems to oppose the role of HDAC4 in synaptic gene expression (Mejat et al. 2005). Whereas HDAC4 induces AChR transcription in denervated muscle (Cohen et al. 2007), MITR represses it (Mejat et al. 2005). It was proposed that MITR repressed AChR expression by recruiting HDAC1 and -3 in order to catalyze histone (H3) deacetylation near myogenic genes. The distinct roles of HDAC4 and MITR/HDAC9 in synaptic gene expression are mirrored by their opposite responses to denervation. As a target gene of MEF2 (Haberland et al. 2007), HDAC9 expression is repressed in denervated muscle (Mejat et al. 2005). Coordinated induction of HDAC4 and repression of MITR would ensure the transcriptional induction of synaptic genes in muscle that lost neural input. How HDAC4 and MITR display opposite activity on synaptic gene transcription is not understood. Given their similar repressive activity on MEF2-dependent transcription, MEF2 is not likely responsible for the transcriptional regulation of synaptic genes. An interesting possibility would be that the catalytic domain of HDAC4, which is lacking in MITR, might play a positive role in instructing the induction of synaptic genes in response to denervation.

HDAC4 is also found concentrated at the NMJ (Cohen et al. 2007). This localization suggests a possibility that HDAC4 might regulate neuromuscular synapses. The most compelling evidence regarding the role of HDAC4 in the motor neuron-myofiber interaction came from the analysis of a micro RNA, miR-206 (Williams et al. 2009). miR-206 is induced in denervated muscle and . In miR-206-deficient mice, reinnervation of the tibialis anterior (TA) muscle following nerve injury is delayed by nearly a week. Based upon computational analysis, HDAC4 is predicted to be a target of miR-206. Indeed, mice carrying a genetic deletion of HDAC4 in skeletal muscle display more rapid reinnervation of myofibers after nerve injury (Williams et al. 2009). It was proposed that HDAC4 affects reinnervation by inhibiting retrograde neurotrophic signaling via fibroblast growth factor 7 (FGF-7), which supports and directs growth of the motor neuron. HDAC4 also regulates the production of large number of cytokines in denervated muscle (TJC, MCC, and TPY, unpublished). It is probable that HDAC4 modulates muscle-axon interactions through multiple cytokines. These findings further underscore the importance of HDAC4 in the communication of neural and muscular compartments. Whether inactivation of HDAC4 could facilitate functional reinnervation in muscles affected by nerve damage would have important therapeutic implication for various neuromuscular disorders. The study of HDAC4 in denervated muscle clearly shows that HDAC4 plays an important role in regulating NMJ through multiple mechanisms.

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