A Novel, Noncanonical BMP Pathway Modulates Synapse Maturation at the Drosophila Neuromuscular Junction

Sulkowski, Mikolaj J.; Han, Tae Hee; Ott, Carolyn; Wang, Qi; Verheyen, Esther M.; Lippincott‐Schwartz, Jennifer; Serpe, Mihaela

doi:10.1371/journal.pgen.1005810

Cited by 56 publications

(84 citation statements)

References 103 publications

(183 reference statements)

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“…Like G9a, mad has been shown to act as both a repressor and an activator of gene transcription, depending on context (16). Although mad is best known for its role in development (17), some studies suggest that it might have regulatory functions in the mature nervous system (18).…”

Section: G9a Wildtypementioning

confidence: 99%

Epigenetic mechanisms modulate differences in Drosophila foraging behavior

Anreiter

Kramer

Sokolowski

2017

Proc. Natl. Acad. Sci. U.S.A.

114

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Little is known about how genetic variation and epigenetic marks interact to shape differences in behavior. The foraging (for) gene regulates behavioral differences between the rover and sitter Drosophila melanogaster strains, but the molecular mechanisms through which it does so have remained elusive. We show that the epigenetic regulator G9a interacts with for to regulate strain-specific adult foraging behavior through allele-specific histone methylation of a for promoter (pr4). Rovers have higher pr4 H3K9me dimethylation, lower pr4 RNA expression, and higher foraging scores than sitters. The rover-sitter differences disappear in the presence of G9a null mutant alleles, showing that G9a is necessary for these differences. Furthermore, rover foraging scores can be phenocopied by transgenically reducing pr4 expression in sitters. This compelling evidence shows that genetic variation can interact with an epigenetic modifier to produce differences in gene expression, establishing a behavioral polymorphism in Drosophila.histone methylation | epigenetics | behavior | foraging | Drosophila melanogaster A lthough it has been shown that variation in human and animal behavior correlates with genetic polymorphisms and epigenetic regulation (1, 2), causal links among genetic variation, epigenetic regulation, and behavior have not been established.The foraging (for) gene in Drosophila melanogaster is a complex gene that encodes several different isoforms of a cGMP-dependent protein kinase (3). for regulates various behavioral and physiological phenotypes in the fly and other organisms, including humans (4-9). Importantly, this gene, with its rover and sitter allelic variants, is known to give rise to naturally occurring behavioral variations in D. melanogaster. Larvae with the rover allele move longer distances while foraging than those with sitter alleles, and the rover allele exhibits genetic dominance over the sitter in this trait (3). for also affects rover-sitter differences in foraging behavior in adult flies (10, 11). These rover-sitter behavioral differences have been shown to arise from genetic variation in the for gene, but until now the molecular mechanisms underlying rover-sitter differences have remained elusive.for has four separate transcription start sites and one transcription termination site encoding at least 21 different transcripts, which cluster into four transcript classes of similar coding sequences according to promoter: pr1, pr2, pr3, and pr4 (4). This complexity could contain the key to understanding the regulation of rover-sitter behavioral differences as well as for's pleiotropic functions. The function of each of for's transcripts and how they are regulated are currently unknown.Epigenetic modifiers play an important role in depositing marks that recruit transcription factors and regulate expression. Drosophila G9a (dG9a, EHMT) is an epigenetic modifier known to methylate the regions of the for promoters (12). G9a is one of three histone methyltransferases that catalyze H3K9me2 in flies. While...

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Section: G9a Wildtypementioning

confidence: 99%

Epigenetic mechanisms modulate differences in Drosophila foraging behavior

Anreiter

Kramer

Sokolowski

2017

Proc. Natl. Acad. Sci. U.S.A.

114

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“…The anti-Brp monoclonal antibody Nc82 utilized here recognizes an epitope on the outer diameter of the T-bars and produces a ring-shaped signal when examined by super-resolution microscopy (Fouquet et al, 2009;Sulkowski et al, 2016). Using 3D structured illumination microscopy (3D-SIM), we measured the maximum diameter of the Brp-marked rings using a line plot across a single z slice (yellow line Figure 2J).…”

Section: Tnc/integrin Complexes Promote the Synaptic Accumulation Of Brpmentioning

confidence: 99%

A presynaptic spectrin network controls active zone assembly and neurotransmitter release

Wang

Friend

Vicidomini

et al. 2019

Preprint

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We have previously reported that Drosophila Tenectin (Tnc) recruits PS2/PS integrin to ensure structural and functional integrity at larval NMJs (Wang et al., 2018). In muscles, Tnc/integrin engages the spectrin network to regulate the size and architecture of synaptic boutons. In neurons, Tnc/integrin controls neurotransmitter release. Here we show that presynaptic Tnc/integrin modulates the synaptic accumulation of key active zone components, including the Ca 2+ channel Cac and the active zone scaffold Brp. Presynaptic α-Spectrin appears to be both required and sufficient for the recruitment of Cac and Brp. We visualized the endogenous α-Spectrin and found that Tnc controls spectrin recruitment at synaptic terminals. Thus, Tnc/integrin anchors the presynaptic spectrin network and ensures the proper assembly and function of the active zones. Since pre-and postsynaptic Tnc/integrin limit each other, we hypothesize that this pathway links dynamic changes within the synaptic cleft to changes in synaptic structure and function. The synaptic extracellular matrix (ECM) contains various synaptic organizers and diffusible molecules that establish and modify synaptic connections during development. ECM receptors, including integrins, transduce these signals by sensing the changes in the synaptic environment and orchestrating the appropriate changes in synapse structure and function (Chavis and Westbrook, 2001;Huang et al., 2006). Disruption of integrins impair synapse development and maturation, neurotransmission, and long-term synaptic plasticity (reviewed in (Park and Goda, 2016)). Integrins together with their ECM ligands form complexes with cytoskeletal proteins and active zone (AZ) components (Carlson et al., 2010;Nishimune et al., 2004;Sunderland et al., 2000). However, it remains unclear how these interactions could influence neurotransmitter release.Spectrin, a principal component of the membrane skeleton, is critical for synaptic transmission (Featherstone et al., 2001;Goodman, 1999). Spectrin subunits function as docking platforms for membrane channels, neurotransmitter receptors and adhesion molecules (reviewed in (Machnicka et al., 2014)). For example, spectrins associate with presynaptic Ca 2+ channels in synaptosome lysates (Carlson et al., 2010;Khanna et al., 2007a;Khanna et al., 2007b). Also, a spectrin-containing presynaptic web enables AZ function in the rodent CNS (Phillips et al., 2001). Recent super-resolution fluorescence microscopy uncovered periodic actin/spectrin lattices along axons, dendrites and spines in a broad range of neuronal cell types (He et al., 2016;Qu et al., 2017;Xu et al., 2013); however, at presynaptic and postsynaptic sites, these patterns were absent (Sidenstein et al., 2016).We have previously found that Drosophila Tenectin (Tnc), an integrin ligand that accumulates in the synaptic cleft at the larval NMJ, modulates synapse development and function (Wang et al., 2018). Tnc recruits αPS2/βPS integrin and forms cis active complexes with distinct pre-and post-synaptic functions....

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“…Mad 7 and Mad 10 are strong alleles with single residue substitutions within the MH2 domain: V419M in Mad 7 and G409S in Mad 10 , respectively (Sekelsky et al, 1995;Takaesu et al, 2005). Both residues map to the L3 loop of the MH2 domain, which has been implicated in mutually exclusive interaction with the type I receptors or with the phosphorylated pS-X-pS tail of adjacent Smads in trimeric complexes (Wu et al, 2001).…”

Section: Strong Mad Alleles Drastically Reduced Both Synaptic and Nucmentioning

confidence: 99%

“…At the opposing pole, the weak Mad 5 and Mad 6 mutants showed no significant changes in either synaptic or nuclear pMad levels during larval stages (Table 2) and had normal larval fat body (not shown). These alleles were isolated independently but have the same single residue change, R272H (Sekelsky et al, 1995;Takaesu et al, 2005).…”

Section: Strong Mad Alleles Drastically Reduced Both Synaptic and Nucmentioning

confidence: 99%

Selective disruption of synaptic BMP signaling by a Smad mutation adjacent to the highly conserved H2 helix

Nguyen

Han

Newfeld

et al. 2019

Preprint

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Bone morphogenetic proteins (BMPs) shape normal development and function via canonical and non-canonical signaling pathways. When activating the canonical pathway, BMPs initiate signaling by binding to transmembrane receptors that phosphorylate pathway effectors, the Smad proteins, inducing their translocation into the nucleus and thus regulation of target genes. Phosphorylated Smads also accumulate at cellular junctions, but this noncanonical signaling modality remains less defined. We have recently reported that phosphorylated Smad (pMad in Drosophila) accumulates at synaptic junctions in complexes with genetically distinct composition and regulation. Here we examined a wide collection of Drosophila Mad alleles and searched for molecular features relevant to pMad accumulation at synaptic junctions. We found that strong Mad alleles generally disrupt both synaptic and nuclear pMad accumulation, whereas moderate Mad alleles have a wider range of phenotypes and could selectively impact different BMP signaling modalities. Interestingly, synaptic pMad appeared more sensitive to net reduction in Mad levels than nuclear pMad. Importantly, a previously uncharacterized allele, Mad 8 , showed markedly reduced synaptic pMad levels but only moderately diminished nuclear pMad signals. The postsynaptic composition and electrophysiological properties of Mad 8 NMJs were similarly altered. Using biochemical approaches, we examined how single point mutations such as S359L, present in Mad 8 , could influence the Mad-receptor interface and we identified a key molecular determinant, the H2 helix. Our study highlights the biological relevance of the Smaddependent, non-canonical BMP signaling and uncovers a highly conserved structural feature of Smads, critical for normal development and function. 1996;Massague, 1990)

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A Novel, Noncanonical BMP Pathway Modulates Synapse Maturation at the Drosophila Neuromuscular Junction

Cited by 56 publications

References 103 publications

Epigenetic mechanisms modulate differences in Drosophila foraging behavior

Epigenetic mechanisms modulate differences in Drosophila foraging behavior

A presynaptic spectrin network controls active zone assembly and neurotransmitter release

Selective disruption of synaptic BMP signaling by a Smad mutation adjacent to the highly conserved H2 helix

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