InteractiveFly: GeneBrief

crimpy: Biological Overview | References

The BMP pathway is essential for scaling of the presynaptic motoneuron arbor to the postsynaptic muscle cell at the Drosophila neuromuscular junction (NMJ). Genetic analyses indicate that the muscle is the BMP-sending cell and the motoneuron is the BMP-receiving cell. Nevertheless, it is unclear how this directionality is established, since Glass bottom boat (Gbb), the known BMP ligand, is active in motoneurons. This study demonstrates that crimpy (cmpy) limits neuronal Gbb activity to permit appropriate regulation of NMJ growth. cmpy was identified in a screen for motoneuron-expressed genes and encodes a single-pass transmembrane protein with sequence homology to vertebrate Cysteine-rich transmembrane BMP regulator 1 (Crim1). A targeted deletion of the cmpy locus was generated, and loss-of-function mutants were found to exhibit excessive NMJ growth. In accordance with its expression profile, tissue-specific rescue experiments indicate that cmpy functions neuronally. The overgrowth in cmpy mutants depends on the activity of the BMP type II receptor Wishful thinking, arguing that Cmpy acts in the BMP pathway upstream of receptor activation and raising the possibility that it inhibits Gbb activity in motoneurons. Indeed, the cmpy mutant phenotype is strongly suppressed by RNAi-mediated knockdown of Gbb in motoneurons. Furthermore, Cmpy physically interacts with the Gbb precursor protein, arguing that Cmpy binds Gbb prior to the secretion of mature ligand. These studies demonstrate that Cmpy restrains Gbb activity in motoneurons. A model is presented whereby this inhibition permits the muscle-derived Gbb pool to predominate at the NMJ, thus establishing the retrograde directionality of the pro-growth BMP pathway (James, 2011).

Motoneurons constitute a fundamental line of communication between the CNS and the periphery. In an anterograde direction, they integrate central interneuron inputs to appropriately depolarize postsynaptic muscle to trigger contractions and stimulate movement. In the retrograde direction, they translate information about muscle activity to modulate synaptic size and strength at the neuromuscular junction (NMJ). Thus, the NMJ is not only a location of neurotransmitter release, but also a primary site of action for pathways that foster communication between synaptic partners. Whereas the directionality of neurotransmission is defined by the inherent cellular asymmetry of pre- and postsynaptic compartments, the directionality of signaling pathway action at the synapse cannot be established in the absence of functional analyses of individual pathway components (James, 2011).

The Wingless/Wnt and bone morphogenetic protein (BMP) morphogens mediate coordinated differentiation of the motoneuron and the muscle cell at the Drosophila NMJ. Forward and reverse genetic approaches have defined pathways that regulate the developmental expansion of the NMJ during larval development. Wingless is released from motoneuron terminals and binds to Frizzled 2 receptors on both the pre- and postsynaptic sides to stimulate NMJ growth and differentiation. The BMP homolog Glass bottom boat (Gbb) has been proposed to act in a retrograde manner to regulate synaptic growth and function (McCabe, 2003). Gbb is postulated to be secreted from the muscle and to bind the type II BMP serine/threonine kinase receptor Wishful thinking (Wit) on presynaptic motoneuron terminals. The Gbb-Wit interaction drives recruitment and activation of a type I receptor - Saxophone (Sax) and/or Thickveins (Tkv). Signal transduction within the motoneuron acts via phosphorylation of the R-Smad Mothers against decapentaplegic (Mad), the association of phospho-Mad with the co-Smad Medea (Med), and the translocation of this complex to the nucleus to elicit changes in gene transcription (James, 2011).

Loss-of-function (LOF) mutants in BMP pathway components result in NMJ undergrowth and impaired basal synaptic transmission at the NMJ. Conversely, elevated BMP signaling, as found in LOF mutants for the inhibitory Smad Daughters against decapentaplegic (Dad) or in larvae expressing the constitutively active type I receptor Tkv, results in substantial expansion of the NMJ. Furthermore, identification of factors that modulate BMP signaling activity on the presynaptic side demonstrates that growth of the motoneuron arbor is exquisitely sensitive to neuronal levels of BMP signal transduction. Additionally, the BMP pathway might serve an anterograde or autocrine function in muscle, as Tkv and phospho-Mad are present in the postsynaptic compartment. However, a function has not been assigned to this pathway, as presynaptic, but not postsynaptic, expression of Mad, Med, Tkv, Sax and Wit rescues the anatomical NMJ defects in the corresponding LOF mutants. Hence, components of the BMP signal transduction cascade are required in motoneurons for developmental NMJ expansion (James, 2011).

Although a number of lines of evidence indicate that motoneurons receive a BMP signal, the source of the signal is less well established. The BMP homolog Gbb is postulated to act retrogradely on the basis of tissue-specific rescue experiments demonstrating that muscle-specific, but not neuron-specific, expression of Gbb in a hypomorphic gbb background rescues NMJ size and bouton number. However, neurotransmitter release at the NMJ is not rescued strongly in these animals. By contrast, basal neurotransmission is fully recovered when Gbb is expressed pan-neuronally in a gbb-deficient background, suggesting the possibility of a presynaptic function for Gbb at the NMJ. Consistent with this model, Gbb is expressed ubiquitously in late embryos. Moreover, a motoneuronal function for Gbb in larvae is strongly implied by functional studies demonstrating that Gbb acts retrogradely in motoneurons to strengthen synaptic transmission with their presynaptic partners. This elegant work established that motoneuronal Gbb is necessary and sufficient to facilitate synaptic excitation between larval motoneurons and presynaptic cholinergic interneurons (James, 2011).

This study identified CG13253, which was named crimpy (cmpy), in a screen for embryonic motoneuron-expressed transcripts. cmpy is predicted to encode a cysteine-rich repeat (CRR)-containing single-pass transmembrane protein, with sequence homology to vertebrate Cysteine-rich transmembrane BMP regulator 1 (Crim1) (Kolle, 2000; Kolle, 2003; Wilkinson, 2003). CRRs are present in a large number of BMP-interacting proteins in vertebrates and invertebrates (Umulis, 2009; Walsh, 2010). This structurally related family includes extracellular antagonists, such as Drosophila Short gastrulation (Sog) and vertebrate Chordin (Chrd), which are believed to interfere with receptor-ligand interactions (see Sog-mediated shuttling of BMPs and the role of membrane-localized reactions). It also includes proteins such as gremlin and sclerostin that can interact with BMPs intracellularly and are thought to interfere with BMP activity, at least in part, by altering ligand activation or secretion. This study presents evidence that Cmpy is a novel antagonist of BMP signaling at the NMJ. It is proposed that Cmpy antagonizes motoneuronal Gbb activity to establish the retrograde directionality of the pro-growth Gbb signal, hence maintaining synchronization of presynaptic axon elaboration and postsynaptic muscle growth (James, 2011).

Gbb has been proposed to cue presynaptic motoneurons to the size of their postsynaptic muscle partners. However, muscles have not been established as the primary source of Gbb at the NMJ. In fact, motoneuron-derived Gbb has a crucial retrograde activity at the motoneuron-interneuron synapse, demonstrating that motoneuronal Gbb is active. The present work demonstrates that motoneurons express Cmpy, a Gbb antagonist. It is proposed that Cmpy restrains motoneuronal activity of Gbb at the NMJ, thus establishing the muscle as the predominant source of the pro-growth BMP signal. Potential mechanisms for Cmpy function at the NMJ and the relationship of Cmpy with intracellular and extracellular BMP antagonists are discussed (James, 2011).

Interest in CG13253/Crimpy was sparked by its restricted expression in the VNC and was reinforced by the presence of a predicted transmembrane domain and CRR. The presence of these two sequence elements renders Cmpy similar to vertebrate Crim1. In mice, Crim1 hypomorphs have been described and display pleiotropic defects in multiple organ systems (Pennisi, 2007). Notably, Crim1 is expressed in developing motoneuron and interneuron populations in the developing mouse and chick spinal cord, although LOF studies have not addressed a neuronal function. A Crim1 homolog has also been described in zebrafish, where it is linked to vascular and somitic development, and in C. elegans, where RNAi-mediated knockdown of crm-1 (cysteine-rich motor neuron protein 1) suggests a pro-BMP function in the control of body size (Fung, 2007). Cell culture studies provide evidence that Crim1 binds Bmp4/7 and antagonizes the production and processing of the preprotein in the Golgi (Wilkinson, 2003). Interestingly, Crim1 interacts with Bmp4/7 at the cell surface and inhibits BMP secretion into the medium (Wilkinson, 2003), raising the possibility that Crim1 antagonizes BMP signaling by multiple cellular mechanisms (James, 2011).

CRR-containing proteins are established modulators of BMP signaling in vertebrates and invertebrates. In Drosophila, posterior wing crossvein specification requires local activation of the BMP pathway, and loss of BMP signaling yields a crossveinless phenotype. BMP ligands are produced in neighboring longitudinal wing veins and are transported to the posterior crossvein. Ligand activity is differentially regulated by the secreted CRR-containing proteins Sog and Crossveinless 2 (Cv-2). Sog and Cv-2 both have pro- and anti-BMP activity, although their mode and range of action differ. Sog is proposed to act at long range, and its anti-BMP activity is thought to derive from sequestering BMPs from their receptors, whereas its pro-BMP activity is likely to arise from transporting BMP ligands through tissues. By contrast, Cv-2 is proposed to act at short range and binds heparan sulfate proteoglycans and the type I receptor Tkv (James, 2011).

The biphasic activities of Sog and Cv-2 serve to emphasize the complex modes of extracellular regulation of BMPs by CRR-containing proteins, as well as to draw attention to possible differences between BMP regulation in the wing and Cmpy-dependent BMP regulation at the NMJ. Although overexpression of Cmpy suppresses Gbb overexpression phenotypes in the wing, cmpy LOF mutants do not display wing vein phenotypes. Cmpy does not function during early embryogenesis, when the BMP homolog Decapentaplegic acts as a classical morphogen in dorsoventral patterning. In both the early embryo and the wing, BMP activity is shaped over many cell diameters by extracellular CRR-containing proteins. Sog and Cv-2 play essential extracellular roles in establishing the magnitude and directionality of BMP signaling. By contrast, Gbb is proposed to act locally at the NMJ to couple pre- and postsynaptic growth (James, 2011).

The close apposition of the cells that send and receive BMP at the NMJ might relieve a requirement for long-range extracellular regulation of the ligand. Instead, it is proposed that a primary challenge at the NMJ is to establish the cellular source of the BMP signal, as Gbb is present both in motoneurons and muscle. In this case, cell-autonomous regulation of the ligand could provide a mechanism for the motoneuron to discriminate between motoneuron- and muscle-derived pools. Consistent with this model, evidence is presented that Cmpy binds Gbb prior to processing and inhibits its growth-promoting activity in motoneurons. In this manner, the Cmpy-Gbb interaction might provide motoneurons with an effective mechanism for distinguishing autocrine and paracrine Gbb signals within the NMJ microenvironment (James, 2011).

CRR-containing BMP antagonists were initially identified from their extracellular roles in the establishment of BMP morphogenetic gradients. It will be interesting to determine whether additional CRR-containing proteins function intracellularly as more short-range BMP-dependent signaling interactions are thoroughly described. Consistent with this idea, several mammalian CRR-containing proteins bind precursor forms of BMP and inhibit BMP activity or secretion in a cell-autonomous manner. Gremlin is a BMP antagonist that is expressed in differentiated cells, including neurons. When co-expressed with Bmp4, gremlin binds to the precursor form of Bmp4 and inhibits secretion. sclerostin, another BMP antagonist, inhibits Bmp7 secretion when the proteins are co-expressed in osteocytes. These studies argue that intracellular modulation of ligand production contributes to BMP signaling directionality in vertebrates (James, 2011).

The work presented in this study suggests that Cmpy antagonizes Gbb activity in motoneurons prior to ligand secretion. To further delineate the Cmpy-Gbb relationship, it will be important to map their localization patterns in motoneurons using compartment-specific markers. Although attempts to generate anti-Cmpy antibodies have been unsuccessful, generation of transgenic flies carrying epitope-tagged Cmpy might enable an analysis of Cmpy subcellular localization. Cmpy-mediated inhibition of Gbb at the NMJ might rely upon restricted localization of Cmpy to this subcellular locale; however, the possibility that Cmpy regulates Gbb activity at the central synapse remains open. Investigation of the localization pattern of Cmpy in motoneurons will begin to address the issue of Cmpy function at these distinct synapses (James, 2011).

An analysis of Gbb distribution, trafficking and secretion in motoneurons in cmpy mutants will indicate the stage of Gbb processing at which Cmpy is likely to act. Studies on mammalian sclerostin provide precedent for an intracellular mechanism for BMP inhibition, as sclerostin sequesters Bmp7 preprotein, leading to its intracellular retention and proteasomal degradation. Interestingly, Cmpy contains only a single, low-threshold CRR. These motifs modulate interactions with mature secreted ligand, suggesting that sequences outside of the CRR mediate interactions with the precursor form of Gbb. Indeed, interaction of Cmpy with Gbb is dependent on C-terminal sequences, including an arginine/lysine-rich domain at the extreme C-terminus. Likewise, the intracellular interaction of gremlin with the precursor form of Bmp4 is not modulated by its cysteine-rich region, but rather by an arginine/lysine-rich domain. The sequence similarities between the BMP interaction domains in gremlin and Crimpy raise the possibility that these proteins antagonize BMP activity by a conserved mechanism (James, 2011).

This study has focused on Cmpy regulation of Gbb in the anatomical development of the NMJ. In addition, Gbb regulates baseline neurotransmission and synaptic homeostasis at the NMJ. Motoneurons precisely compensate for impaired postsynaptic neurotransmitter receptor sensitivity by increasing presynaptic neurotransmitter release. This homeostatic response requires Gbb, which is not itself the acute retrograde homeostatic signal but rather establishes the competence of motoneurons to receive the homeostatic signal. A number of genetic manipulations indicate that the roles of Gbb in regulating synaptic homeostasis, basal neurotransmission and NMJ morphology are separable. Perhaps surprisingly, neuron-specific Gbb rescues both synaptic homeostasis and baseline neurotransmitter release in gbb null animals. By contrast, whereas muscle-derived Gbb rescues synaptic homeostasis in gbb null animals, it does not significantly rescue baseline synaptic function, arguing that neuronal- and muscle-derived pools of Gbb serve distinct functions. Although the data indicate that Cmpy antagonizes autocrine Gbb signaling in motoneurons to restrain morphological expansion at the NMJ, it is likely that motoneuronal Gbb has an independent role in regulating functional development of the NMJ. If so, the Cmpy-Gbb complex might be active and could elicit a signaling outcome distinct from that of the muscle-derived pool of Gbb. Physiological analyses of cmpy mutants, as well as an investigation of Gbb trafficking and secretion at the NMJ in cmpy mutants, should provide crucial insight into this important question (James, 2011).

More broadly, this study is of relevance to the regulation of signal release in neurons. By definition, neurotransmitter is released from the presynaptic compartment and received by neurotransmitter receptors on the postsynaptic side. However, signaling pathway activity is not circumscribed in this way and may occur at short or long range at multiple subcellular positions. Hence, neurons are likely to possess fine-regulatory mechanisms controlling the release of, and response to, extracellular cues. The present work provides insight into the regulation of signaling molecules in neurons and suggests that the mechanisms that control signaling specificity in the developing nervous system are only beginning to be uncovered (James, 2011).

Crimpy enables discrimination of presynaptic and postsynaptic pools of a BMP at the Drosophila neuromuscular junction

Distinct pools of the bone morphogenetic protein (BMP) Glass bottom boat (Gbb) control structure and function of the Drosophila neuromuscular junction. Specifically, motoneuron-derived Gbb regulates baseline neurotransmitter release, whereas muscle-derived Gbb regulates neuromuscular junction growth. Yet how cells differentiate between these ligand pools is not known. This study presents evidence that the neuronal Gbb-binding protein Crimpy (Cmpy) permits discrimination of pre- and postsynaptic ligand by serving sequential functions in Gbb signaling. Cmpy first delivers Gbb to dense core vesicles (DCVs) for activity-dependent release from presynaptic terminals. In the absence of Cmpy, Gbb is no longer associated with DCVs and is not released by activity. Electrophysiological analyses demonstrate that Cmpy promotes Gbb's proneurotransmission function. Surprisingly, the Cmpy ectodomain is itself released upon DCV exocytosis, arguing that Cmpy serves a second function in BMP signaling. In addition to trafficking Gbb to DCVs, it is proposed that Gbb/Cmpy corelease from presynaptic terminals defines a neuronal protransmission signal (James, 2014).

Growth factors regulate morphological and electrophysiological attributes of synapses. In Drosophila, the bone morphogenetic protein (BMP) pathway regulates neuromuscular junction (NMJ) development and function. In the traditional view, the pathway acts in a retrograde direction to coordinate pre- and postsynaptic growth. However, the pathway regulates more than morphological expansion: BMP pathway mutants also exhibit profound deficits in active zone organization, baseline neurotransmitter release, and synaptic homeostasis. These phenotypes suggest distinct functions for BMP signaling at the NMJ. Indeed, tissue-specific rescue experiments demonstrate that progrowth and protransmission functions are at least partially separable. Although muscle-specific expression of the BMP ligand Glass bottom boat (Gbb) rescues NMJ morphology in gbb mutants, it does not rescue baseline neurotransmission. Neuron-specific Gbb expression is required for normal baseline neurotransmitter release (Goold, 2007). These data raise the possibility of distinct ligand pools at the NMJ. How are pre- and postsynaptic pools of Gbb distinguished (James, 2014)?

A previous study found that Crimpy (Cmpy) prevents motoneuron-derived Gbb from driving excessive growth at the NMJ (James, 2011). Cmpy was identified in a screen for motoneuron-expressed genes and codes for a single-pass transmembrane protein that physically interacts with Gbb. It has sequence homology to the vertebrate transmembrane BMP-binding protein Crim1 (Cysteine-rich in motoneurons-1). Loss of Cmpy results in NMJ overgrowth, which is rescued by knockdown of Gbb in motoneurons. Thus, neuronal Gbb drives excessive NMJ growth in cmpy mutants. Because neuronal Gbb normally promotes neurotransmitter release, the finding that it promotes NMJ growth in cmpy mutants suggested a possible transformation of presynaptic Gbb from a proneurotransmission to a progrowth signal (James, 2014).

To shed light on the role of Cmpy in Gbb regulation, this study set out to characterize the presynaptic Gbb pool. In general, proteins are secreted from neurons via one of two major secretory routes: the constitutive secretory pathway (CSP) and the regulated secretory pathway (RSP). Vesicles in the CSP spontaneously fuse with the plasma membrane to release their contents. In contrast, vesicles in the RSP undergo Ca2+-regulated exocytosis in response to neuronal activity. These pathways bifurcate in the trans-Golgi network, where proteins destined for the RSP are packaged into dense core vesicles (DCVs) and trafficked to the synapse for activity-dependent release. In the absence of specialized sorting signals/cofactors delivering proteins to the RSP, they are shunted into the CSP for constitutive release (James, 2014).

This study found that neuronal Gbb is normally trafficked to presynaptic terminals at the NMJ. Levels of presynaptic Gbb are proportional to levels of Cmpy, and Cmpy and Gbb associate with dense core vesicles (DCVs). Arguing that Cmpy delivers neuronal Gbb to DCVs for Ca2+-regulated release, presynaptic Gbb release is absolutely dependent on both synaptic activity and Cmpy. These data provide evidence that Cmpy is a DCV sorting receptor for Gbb. The proposed transformation of presynaptic Gbb from proneurotransmission to progrowth signaling in cmpy mutants suggests that Cmpy marks the proneurotransmission pool. In support of this hypothesis, Cmpy is necessary for the ability of presynaptic Gbb to fully rescue neurotransmitter release in gbb mutants. Moreover, evidence is provided that the Cmpy ectodomain is secreted following nerve depolarization, arguing that Cmpy serves sequential functions in synaptic BMP signaling. It is proposed that Cmpy first delivers Gbb to DCVs and is then coreleased with Gbb to define a presynaptic proneurotransmission signal (James, 2014).

Crimpy prevents neuronal Gbb from driving excessive NMJ growth (James, 2011). To understand Cmpy-mediated regulation of Gbb, this study investigated its mechanism of action. Cmpy was found to control Gbb trafficking to presynaptic terminals, suggesting that it promotes Gbb function at synapses. Indeed, evidence is provided that Cmpy sorts Gbb into an activity-regulated pool that promotes baseline synaptic transmission. These studies suggest a mechanistic explanation for the proposed switch in signaling identity of neuronal Gbb in cmpy mutants. It is proposed that loss of Cmpy results in inappropriate NMJ growth because neuronal Gbb, which is normally destined for DCVs and released with the Cmpy ectodomain, is shunted into the CSP. It is further proposed that in cmpy mutants, constitutively secreted neuronal Gbb is misinterpreted by the neuron as muscle-derived progrowth signal, leading to NMJ overgrowth. This model is consistent with studies of protein trafficking in mammalian neurons, which have defined constitutive secretion as the default secretory pathway. For example, brain-derived neurotrophic factor (BDNF) secretion is regulated by neuronal activity. Sorting of BDNF into the regulated secretory pathway is mediated by Sortilin and Carboxypeptidase E. Loss of either protein results in BDNF missorting into the constitutive secretory pathway and enhanced constitutive release. Loss of intrinsic sorting signals also leads to missorting, because mutation of a dileucine-like sorting motif in the vesicular monoamine transporter 2 (VMAT2) diverts VMAT2 from the regulated to the constitutive secretory pathway. Consistent with the hypothesis that neuronal Gbb is missorted and constitutively released in the absence of Cmpy, abundant extracellular Gbb-HA is detected in the absence of stimulation in cmpy nulls (James, 2014).

Muscle-derived Gbb synchronizes morphological growth of pre- and postsynaptic cells, whereas neuron-derived Gbb regulates neurotransmitter release. This study found that Cmpy is required for activity-dependent release of Gbb. It is conceivable that either the location or timing of activity-dependent Gbb release at the NMJ is sufficient to define the presynaptic Gbb pool. It is alternatively possible that Gbb in DCVs in the regulated secretory pathway is processed differently than Gbb in the constitutive secretory pathway. In either case, Cmpy-dependent transport of Gbb to the regulated pathway would serve to mark motoneuron-derived Gbb. Further analysis of Gbb release and processing in cmpy mutants will define precisely the Cmpy-dependent DCV pool (James, 2014).

These studies suggest that Cmpy serves a second function in BMP signaling. The data suggest that a cleaved C-terminal fragment of Cmpy may be secreted with Gbb at the NMJ. Ectodomain shedding of Cmpy is consistent with the identification of a C-terminal cleavage product with Gbb-binding activity (James, 2011). In support of this model, the Cmpy C terminus is itself subject to activity-dependent release. Drosophila Crimpy shares sequence homology with the vertebrate transmembrane protein Crim1 (Cysteine-rich in motoneurons-1). Crim1 interacts with BMP4 and BMP7 and is expressed in motoneuron and interneuron populations in the developing spinal cord, though loss-of-function studies have not uncovered its neuronal function. Significantly, Crim1 is subject to a juxtamembrane cleavage that generates a secreted ectodomain that binds BMPs. Ectodomain shedding of Crim1 is consistent with the proposed secretion of the Cmpy ectodomain and suggests that the proteins serve similar functions. The proposed sequential roles for Cmpy in Gbb trafficking and signaling are also reminiscent of Sortilin's roles in successive aspects of neurotrophin signaling: Sortilin not only delivers BDNF into the regulated secretory pathway, but also forms a complex with the p75NTR receptor to drive cell death. Hence, Sortilin enables separation of proapoptosis and prosurvival signal transduction cascades. As an important test of Cmpy's signaling role, it will be critical to establish whether Cmpy cleavage is essential for its function and if a Cmpy-Gbb complex is secreted from neurons. Although Cmpy processing and release was detected, it is possible that full-length Cmpy acts as a BMP coreceptor and that Cmpy is cleaved only after its signaling function is complete. Testing for physical interactions between both cleaved and full-length Cmpy and the neuronal BMP receptors may shed light on the relationship between Cmpy processing and its biological activity (James, 2014).

The distinct signaling outcomes of muscle-derived progrowth signaling and neuron-derived protransmission signaling imply at least partially independent molecular cascades. Hence, it should, in principle, be possible to identify mutants required for growth, and not transmission, and vice versa (James, 2014).

Motoneurons express canonical members of the BMP signal transduction machinery, including the type II receptor Wishful thinking, the type I receptors Saxophone and Thickveins, the R-Smad Mad, and the co-Smad Medea. Loss-of-function mutations in these genes result in NMJ undergrowth and defective synaptic transmission, suggesting they regulate both synaptic size and strength. However, it is also possible that the transmission defects are secondary to the severe NMJ growth defects in these backgrounds, obscuring the identities of components dedicated to progrowth signaling. Conversely, genes required specifically for synaptic transmission would not have been identified in large-scale screens for aberrant NMJ morphology. Dissection of the roles of individual BMP signaling components in both muscle and neuron-derived Gbb signaling will be essential to tease apart the signal transduction cascades (James, 2014).

Regarding pathway directionality, firm evidence indicates that the progrowth pathway acts in a retrograde direction; however, the directionality of the protransmission pathway is incompletely defined. While an autocrine signaling mechanism provides the most parsimonious explanation for the current findings, a requirement for postsynaptic muscle in protransmission signaling cannot be ruled out. The data do not exclude the possibility that motoneuron-derived Gbb induces a postsynaptic signal that in turn promotes neurotransmitter release. Given the number and complexity of signaling interactions at the NMJ), it will be crucial to test if components of the BMP signal transduction machinery display postsynaptic requirements for neurotransmitter release (James, 2014).

BMP/TGF-β ligands regulate plasticity, cognition, and affective behavior in mammals. Arguing for local and specific synaptic action, mammalian BMP/TGF-β family members are sorted into secretory vesicles and subject to activity-dependent release. Given clinical interest in targeting synaptic functions of neuromodulators, a mechanistic understanding of Crimpy and its mammalian homologs will be of interest (James, 2014).

Search PubMed for articles about Drosophila Crimpy

Fung, W. Y., Fat, K. F., Eng, C. K. and Lau C. K. (2007). crm-1 facilitates BMP signaling to control body size in Caenorhabditis elegans. Dev. Biol. 311: 95-105. PubMed ID: 17869238

Goold, C. P. and Davis, G. W. (2007). The BMP ligand Gbb gates the expression of synaptic homeostasis independent of synaptic growth control. Neuron 56: 109-123. PubMed ID: 17920019

James, R. E. and Broihier, H. T. (2011). Crimpy inhibits the BMP homolog Gbb in motoneurons to enable proper growth control at the Drosophila neuromuscular junction. Development 138(15): 3273-86. PubMed ID: 21750037

James, R. E., Hoover, K. M., Bulgari, D., McLaughlin, C. N., Wilson, C. G., Wharton, K. A., Levitan, E. S. and Broihier, H. T. (2014). Crimpy enables discrimination of presynaptic and postsynaptic pools of a BMP at the Drosophila neuromuscular junction. Dev Cell 31: 586-598. PubMed ID: 25453556

Kolle G., et al. (2000). CRIM1, a novel gene encoding a cysteine-rich repeat protein, is developmentally regulated and implicated in vertebrate CNS development and organogenesis. Mech. Dev. 90: 181-193. PubMed ID: 10642437

Kolle, G., Jansen, A., Yamada, T. and Little, M. (2003). In ovo electroporation of Crim1 in the developing chick spinal cord. Dev. Dyn. 226: 107-111. PubMed ID: 12508231

McCabe, B. D., et al. (2003). The BMP homolog Gbb provides a retrograde signal that regulates synaptic growth at the Drosophila neuromuscular junction. Neuron 39: 241-254. PubMed ID: 12873382

Pennisi D. J., et al. (2007). Crim1KST264/KST264 mice display a disruption of the Crim1 gene resulting in perinatal lethality with defects in multiple organ systems. Dev. Dyn. 236: 502-511. PubMed ID: 17106887

Umulis, D., O'Connor M. B. and Blair, S. S. (2009). The extracellular regulation of bone morphogenetic protein signaling. Development 136: 3715-3728. PubMed ID: 9855014

Walsh, D. W., et al. (2010). Extracellular BMP-antagonist regulation in development and disease: tied up in knots. Trends Cell Biol. 20: 244-256. PubMed ID: 20188563

Wilkinson, L., et al. (2003). CRIM1 regulates the rate of processing and delivery of bone morphogenetic proteins to the cell surface. J. Biol. Chem. 278: 34181-34188. PubMed ID: 12805376

date revised: 27 May 2012

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