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• W2609251707 abstract "Synaptic plasticity occurs in response to intrinsic and extrinsic cues and is a key step in the formation of mature neuronal circuits. In this issue of Developmental Cell, Meng et al., 2017Meng J. Ma X. Tao H. Jin X. Witvliet D. Michell J. Zhu M. Dong M.-Q. Zhen M. Jin Y. Qi Y.B. Dev. Cell. 2017; 41 (this issue): 180-194Scopus (17) Google Scholar find that two conserved Myrf transcription factors coexist in the same complex to promote developmental circuit remodeling. Synaptic plasticity occurs in response to intrinsic and extrinsic cues and is a key step in the formation of mature neuronal circuits. In this issue of Developmental Cell, Meng et al., 2017Meng J. Ma X. Tao H. Jin X. Witvliet D. Michell J. Zhu M. Dong M.-Q. Zhen M. Jin Y. Qi Y.B. Dev. Cell. 2017; 41 (this issue): 180-194Scopus (17) Google Scholar find that two conserved Myrf transcription factors coexist in the same complex to promote developmental circuit remodeling. The ability of neuronal connections to change over time is called synaptic plasticity. Plasticity can occur on a relatively small scale via modulation of the size or strength of individual synapses. It also occurs on a larger scale through wholesale elimination of existing synapses or formation of new synapses. Whereas in some contexts, synaptic plasticity is activity dependent and influenced by experience or the environment, in others it is genetically programmed and highly stereotyped. The genetic programs driving these stereotyped changes in circuit architecture are just coming into focus. In the current issue of Developmental Cell, Meng et al., 2017Meng J. Ma X. Tao H. Jin X. Witvliet D. Michell J. Zhu M. Dong M.-Q. Zhen M. Jin Y. Qi Y.B. Dev. Cell. 2017; 41 (this issue): 180-194Scopus (17) Google Scholar have identified two transcription factors, the paralogs Myrf-1 and Myrf-2, that together direct developmental circuit rewiring in C. elegans. C. elegans Dorsal D (DD) GABAergic motoneurons provide a dramatic example of stereotyped developmental circuit plasticity and are an ideal model to dissect molecular mechanisms governing this process. DD neurons rewire their connections during development via coordinated elimination of existing synapses and formation of new ones (White et al., 1978White J.G. Albertson D.G. Anness M.A. Nature. 1978; 271: 764-766Crossref PubMed Scopus (123) Google Scholar, Hallam and Jin, 1998Hallam S.J. Jin Y. Nature. 1998; 395: 78-82Crossref PubMed Scopus (141) Google Scholar). During early development, these neurons receive cholinergic input on their dorsal processes and send GABAergic output onto ventral muscles. At the end of the LI stage, these connections change. DD neurons begin to receive input from newly born ventral cholinergic neurons and shift their synaptic output onto dorsal muscles (Figure 1). To enable this rewiring, ventral synapses are eliminated and new dorsal synapses form. The genetic mechanisms establishing these changes are largely obscure. The Lin-14 transcription factor has been shown to prevent premature DD rewiring via regulation of a synaptic organizer called Oig-1 (Hallam and Jin, 1998Hallam S.J. Jin Y. Nature. 1998; 395: 78-82Crossref PubMed Scopus (141) Google Scholar, He et al., 2015He S. Philbrook A. McWhirter R. Gabel C.V. Taub D.G. Carter M.H. Hanna I.M. Francis M.M. Miller 3rd, D.M. Curr. Biol. 2015; 25: 2541-2548Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, Howell et al., 2015Howell K. White J.G. Hobert O. Nature. 2015; 523: 83-87Crossref PubMed Scopus (42) Google Scholar). However, the molecular factors essential to promote DD synapse rewiring remain unclear. In a forward genetic screen for mutants with altered DD neuron rewiring, Meng et al., 2017Meng J. Ma X. Tao H. Jin X. Witvliet D. Michell J. Zhu M. Dong M.-Q. Zhen M. Jin Y. Qi Y.B. Dev. Cell. 2017; 41 (this issue): 180-194Scopus (17) Google Scholar isolated a mutation (ju1121) that blocked formation of presynaptic specializations in dorsal DD neurites. Genetic analyses demonstrated that the causative mutation results in an amino acid substitution at a conserved residue within the predicted DNA binding domain of Myrf-1. Myrf-1 and Myrf-2 are homologs of the mammalian Myelin regulatory factor (MYRF) transcription factor, which is required for Myelin development in oligodendrocytes (Emery et al., 2009Emery B. Agalliu D. Cahoy J.D. Watkins T.A. Dugas J.C. Mulinyawe S.B. Ibrahim A. Ligon K.L. Rowitch D.H. Barres B.A. Cell. 2009; 138: 172-185Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar). In the course of a systematic genetic analysis, the authors surprisingly found that three preexisting myrf-1 alleles, as well as newly generated deletion alleles, did not block DD rewiring. As a result, the authors hypothesized that Myrf-2, which is 80% similar to Myrf-1 at the amino acid level, functioned redundantly with Myrf-1 in DD rewiring. To test this hypothesis, they generated myrf-1(null); myrf-2(null) double mutants and found that these mutants eliminate DD rewiring akin to ju1121. The authors next performed an impressive series of biochemical and genetic experiments to understand the mechanism by which ju1121 prevents rewiring. Through these experiments, Meng et al., 2017Meng J. Ma X. Tao H. Jin X. Witvliet D. Michell J. Zhu M. Dong M.-Q. Zhen M. Jin Y. Qi Y.B. Dev. Cell. 2017; 41 (this issue): 180-194Scopus (17) Google Scholar found that ju1121 acts as a dominant-negative Myrf-1 allele and so can block DNA binding of not only Myrf-1 but also Myrf-2. These findings explain why ju1121 is sufficient to inhibit synapse rewiring and indicate that Myrf-1 and Myrf-2 function redundantly in this context. Meng et al., 2017Meng J. Ma X. Tao H. Jin X. Witvliet D. Michell J. Zhu M. Dong M.-Q. Zhen M. Jin Y. Qi Y.B. Dev. Cell. 2017; 41 (this issue): 180-194Scopus (17) Google Scholar employed multiple strategies to demonstrate specific and cell-autonomous roles for Myrf-1/2 in DD rewiring. They show that in ju1121 animals, neurogenesis and initial synaptogenesis of DD neurons is unaffected and synaptic morphologies of other neurons in the motor circuit are normal. They also performed cell-type-specific rescue experiments demonstrating that Myrf-1/2 function is required in DD neurons to promote synaptic rewiring. The authors next sought to define the mechanism of action of Myrf-1/2. An earlier study in C. elegans found that Myrf-1 was predominantly endoplasmic reticulum (ER) localized (Russel et al., 2011Russel S. Frand A.R. Ruvkun G. Dev. Biol. 2011; 360: 297-309Crossref PubMed Scopus (24) Google Scholar). Intriguingly, mammalian studies showed that MYRF proteins undergo autocleavage in the ER membrane to separate a C-terminal transmembrane domain from an N-terminal DNA binding domain that translocates into the nucleus following cleavage (Bujalka et al., 2013Bujalka H. Koenning M. Jackson S. Perreau V.M. Pope B. Hay C.M. Mitew S. Hill A.F. Lu Q.R. Wegner M. et al.PLoS Biol. 2013; 11: e1001625Crossref PubMed Scopus (159) Google Scholar, Li et al., 2013Li Z. Park Y. Marcotte E.M. PLoS Biol. 2013; 11: e1001624Crossref PubMed Scopus (43) Google Scholar). To establish localization of Myrf-1/2 in DD neurons, Meng et al., 2017Meng J. Ma X. Tao H. Jin X. Witvliet D. Michell J. Zhu M. Dong M.-Q. Zhen M. Jin Y. Qi Y.B. Dev. Cell. 2017; 41 (this issue): 180-194Scopus (17) Google Scholar designed functional Myrf-1 and Myrf-2 mini genes with distinct tags in N-terminal regions and at the C-terminal ends. Using the mini genes, the authors found that the N and C termini of Myrf-1 and Myrf-2 are differentially localized. While MYRF C termini display significant colocalization with ER markers, their N termini are nuclear (Figure 1). This striking difference in localization suggested the possibility of proteolysis of the MYRFs into N- and C-terminal fragments. Indeed, the authors find that both proteins are cleaved in vivo. Like their mammalian counterparts, Myrf-1/2 contain highly conserved Chaperone of Endosialidase domains that catalyze intramolecular cleavage. To test whether a similar mechanism might be at play in DD neurons, the authors generated a non-cleavable mutant of Myrf-1 and found that expression of this mutant fails to rescue DD remodeling in myrf-1 mutants, demonstrating that Myrf-1 cleavage is essential for its function. The similar domain structure of Myrf-1 and Myrf-2, as well as the dominant-negative activity of ju1121, raised the possibility that the proteins form hetero-oligomers in the ER. In agreement with this hypothesis, the proteins reciprocally co-immunoprecipitate. Further supporting a Myrf-1/2 protein complex, overexpression of non-cleavable Myrf-1 had dominant-negative activity and blocked Myrf-2 function, presumably by impeding its translocation into the nucleus. Altogether, these findings argue that a Myrf-1/2 protein complex is present on the ER. This complex undergoes intramolecular cleavage, releasing an N-terminal DNA binding domain that translocates to the nucleus and likely regulates downstream gene expression essential for DD remodeling. As a final test of whether Myrf-1/2 serve as instructive cues for DD remodeling, the authors investigated whether MYRF overexpression can drive premature DD wiring. Indeed, overexpression of active forms of Myrf-1/2 accelerated synapse plasticity, arguing that nuclear translocation of an N-terminal Myrf-1/2 protein complex triggers coordinated disassembly of ventral synapses and assembly of dorsal synapses in DD neurons. This exciting study raises a number of interesting questions. First, are there evolutionarily conserved aspects of MYRF protein function in the nervous system? In the mammalian CNS, Myrf is expressed specifically in oligodendrocytes where it directs Myelin development and maturation (Emery et al., 2009Emery B. Agalliu D. Cahoy J.D. Watkins T.A. Dugas J.C. Mulinyawe S.B. Ibrahim A. Ligon K.L. Rowitch D.H. Barres B.A. Cell. 2009; 138: 172-185Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar). Because C. elegans neurons are not myelinated, MYRF proteins’ namesake function is not conserved. However, it is conceivable that the family plays conserved roles in orchestrating terminal differentiation. Just as myelination is central to oligodendrocyte maturation, synaptic plasticity is central to DD neuron maturation. A mechanistic understanding of how MYRF proteins direct terminal differentiation in these disparate contexts will shed light on this issue. Second, is Myrf-1/2 cleavage constitutive or regulated? While it is established that MYRF proteins have autoproteolytic activity, it is not clear whether the proteolysis in DD neurons requires additional factors or is constitutive. This is essential to investigate because Myrf-1/2 proteolysis presumably sets the timing for DD neuron rewiring. And lastly, what are the downstream transcriptional targets of Myrf-1/2? Cell biological mechanisms underpinning DD rewiring are beginning to be defined. Synaptic microtubule dynamics increase 2-fold at the onset of remodeling, and this increase is necessary for remodeling to occur (Kurup et al., 2015Kurup N. Yan D. Goncharov A. Jin Y. Curr. Biol. 2015; 25: 1594-1605Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Identification of the Myrf-1/2-dependent transcriptome will establish whether these critical transcription factors are linked to changes in trafficking, delivery, or dynamics of key synaptic components. Myrf ER-Bound Transcription Factors Drive C. elegans Synaptic Plasticity via Cleavage-Dependent Nuclear TranslocationMeng et al.Developmental CellApril 24, 2017In BriefSynaptic rewiring of DD neurons in C. elegans provides a powerful in vivo model to study developmental plasticity of the nervous system. Meng et al. identified myrf-1 and myrf-2, members of the Myelin Regulatory Factor family of transcription factors, as essential regulators that drive synaptic rewiring via a cleavage-dependent mechanism. Full-Text PDF Open Archive" @default.
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• W2609251707 title "MYRFs on the Move to Rewire Circuits" @default.
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