- Email: [email protected]
Neuroscience: The Hidden Diversity of Electrical Synapses
Current Biology
Dispatches regardless of where in the forest the male- and female-skewed populations were located. Finally, manipulating adult sex ratios in large populations of mobile organisms such as birds seems perilous, as the animals are likely to disperse and balance out the targeted local sex ratio biases. To some extent, this was the case for female-skewed plots (where females dispersed from them and consequently the adult sex ratio became close to even; Figure 2), but male brown-headed nuthatches did not disperse far, leading to heavily maleskewed plots. Intriguingly, the presence of surplus males had a self-reinforcing effect: male offspring that hatched in the maleskewed plots were more likely to stay, and, surprisingly, male-skewed plots appeared to attract males from the outside. The result not only provides the key information that mate shortage leads to postponed independent breeding but also raises intriguing new questions: how do animals perceive skewed adult sex ratios? Do young
individuals use social information to help them decide whether to stay as subordinate in a group or disperse and became an independent breeder? The presence of surplus males may attract more males because in natural settings it would reflect a high-quality habitat. As nuthatch helpers are often unrelated to the family they join, the direct benefits of helping, such as access to food and mates and to a potential territory in the future, may thus be important drivers for individuals to stay and help. Therefore, Cox and colleagues [4] made a major step towards uncovering the role of a demographic trait (adult sex ratio) in a puzzling social behaviour (cooperative breeding), and their results open an exciting avenue for future research into how social information affects breeding systems.
2. Darwin, C. (1859). On the Origin of Species by Means of Natural Selection (London: Murray). 3. Cockburn, A. (1998). Evolution of helping behavior in cooperatively breeding birds. Annu. Rev. Ecol. Syst. 29, 141–177. 4. Cox, J.A., Cusick, J.A., and DuVal, E.H. (2019). Manipulated sex ratios alter group structure and cooperation in the brown-headed nuthatch. Behav. Ecol. https://doi.org/10.1093/beheco/ arz030. kely, T., Bessinger, S., and 5. Jennions, M., Sze Kappeler, P.M. (2017). Sex ratios. Curr. Biol. 27, R790–R792. kely, T., Weissing, F.J., and Komdeur, J. 6. Sze (2014). Adult sex ratio variation: implications for breeding system evolution. J. Evol. Biol. 27, 1500–1512. kely, T., and 7. Schacht, R., Kramer, K.L., Sze Kappeler, P.M. (2017). Adult sex ratios and reproductive decisions: a critical reexamination of sex differences in human and animal societies. Philos. Trans. R. Soc. B 372, 20160309.
REFERENCES
kely, T., Long, X., and Kingma, 8. Komdeur, J., Sze S.A. (2017). Adult sex ratios and the implications for cooperative breeding in birds. Philos. Trans. R. Soc. B 372, 20160322.
1. Koenig, W.D., and Dickinson, J. (2016). Cooperative Breeding in Vertebrates: Studies of Ecology, Evolution and Behavior (Cambridge: Cambridge University Press).
kely, T. 9. Liker, A., Freckleton, R.P., and Sze (2013). The evolution of sex roles in birds is related to adult sex ratio. Nat. Commun. 4, 1587.
Neuroscience: The Hidden Diversity of Electrical Synapses Alberto E. Pereda Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA Correspondence: [email protected] https://doi.org/10.1016/j.cub.2019.04.002
The complete description of the expression of gap junction proteins in the nervous system of the worm reveals a great complexity of their distribution amongst different neuronal classes, opening an unprecedented opportunity to expose the functional diversity of electrical synapses. Interconnected neurons communicate with each other at structures named synapses, where information is mediated via either the release of a transmitter substance (‘chemical synapses’) or the spread of electrical currents at a direct communicating pathway formed by aggregates of intercellular channels known as ‘gap junctions’ (‘electrical synapses’), a prevalent form of signaling in neurons (Figure 1A). Chemical
synapses are known to be functionally diverse by combining different modalities of release, neurotransmitters and receptors. In contrast, the diversity of electrical synapses is less known. A potential mechanism for diversity in electrical synapses lies in the identity of the gap junction channel-forming proteins, named ‘connexins’ and ‘innexins’ in vertebrates and invertebrates, respectively [1]. Since the
R372 Current Biology 29, R358–R380, May 20, 2019 ª 2019 Elsevier Ltd.
intercellular channel is formed by the docking of two channels, or ‘hemichannels’, each provided by one of the contacting cells, it is possible to have intercellular channels made by hemichannels formed by a single protein (homotypic intercellular channel), two different proteins (heterotypic intercellular channel) or by heteromeric channels in either homotypic or heterotypic configurations (Figure 1B) [2].
Current Biology
Dispatches A report by Bhattacharya et al. that recently appeared in the journal Cell [3] provides a full description of the expression pattern of innexins in the neurons of the worm Caenorhabditis elegans nervous system, thus exposing the distribution of electrical synapses, or ‘electrical connectome’, of this model organism. The work represents an authentic tour de force and the first full description of an electrical connectome of any nervous system. The report shows that 14 of the 25 C. elegans innexin genes are expressed in neurons and that all of the 118 neuron classes of this worm express innexins. Interestingly, most neurons express multiple innexins and more than 30 neurons express at least 10 innexins (maximum 11) (Figure 2A). In contrast, one innexin (eat-5) is expressed in only one neuron class. Remarkably, 98 of the 118 neuron classes expressed unique combinations of innexins. With a few exceptions, this distribution was found to be stable in larval stages and the adult worm, suggesting that different innexins or channels formed by combinations of them are capable of providing diversity of electrical communication within this nervous system. The full extent of the functional differences brought by different innexins remains to be determined. We know, for example, that heterotypic gap junction channels are generally associated with rectification (preferential current flow in one direction) of electrical transmission [2]. In addition to the exhaustive description of the electrical connectome, the study also provides evidence that the wiring formed by the expression of these proteins is plastic, that is, it can under some circumstances be modified. Under challenging envirommental conditions C. elegans larvae undergo an arrest (a type of stasis or period of inactvity) named dauer, during which the larvae can survive harsh conditions. The study found that 11 of the 14 innexins were modified (their expression increased or decreased) and these changes were observed in 86 of the 118 neuron classes (Figure 2B). Some changes were specific: eat-5 was exclusively reduced in the AWA cell and, strikingly, inx-6 was expressed in AIB cells only in the dauer state. The dauer-specific expression of
A Gap junction Neuron 1
Neuron 2
Heteromeric heterotypic
Homotypic
B
Cell 1 Cell 2
Heterotypic
Heteromeric homotypic Current Biology
Figure 1. Gap junctions mediate synaptic transmission between neurons. (A) Gap junctions (Gap junction, blue) are aggregates of intercellular channels formed by the docking of two ‘hemichannels’, each contributed by one of the connected cells. Gap junctions allow electrical and chemical synaptic communication between two adjacent cells (arrows). (B) Intercellular channels might exist in different configurations. The cartoon summarizes the possible configurations formed by two different channel forming proteins (vertebrate connexins or invertebrate innexins) represented here by red and green colors (Cell 1 and Cell 2 indicate the membrane of each cell).
inx-6 (innexin 6, INX-6) provided the opportunity to examine in detail the state-dependent changes as well as to expose the molecular triggers of these changes. In an elegant set of experiments demonstrating the utility of C. elegans for exploring mechanistic insights, the study finds that INX-6 forms dauer-specific homotypic gap junctions between the right and the left AIB cells and heterotypic channels with the BAG cell, which instead expresses the CHE-7 innexin (Figure 2C). In other words, two different types of electrical synapses are formed by AIB cells during this stage. Furthermore, this rewiring was linked to the altered locomotor and chemosensory behaviors of the dauer larva. Finally, the authors identified the gene regulatory mechanism mediating the dauer-specific expression of inx-6, involving terminal selector and FoxO transcription factors. Thus, the expression of specific innexins is capable of providing functional differences, further suggesting that the
diversity of innexin proteins likely constitutes a source of functional diversity for electrical synapses. The description of the connectome of a given nervous system is arguably necessary but not sufficient to understand the behavior of neural networks, a catalog of possible connections of overlapping networks of chemical and electrical synapses whose functional states can be regulated by neurotransmitter modulators to reconfigure circuits [4]. The study by Bhattacharya et al. [3] shows that hardwired connectomes are, under certain conditions, also modifiable. It is presently unclear if this remodeling of the connectome is only due to the extreme conditions of the dauer larva or can also occur, perhaps to a lesser extent, under normal physiological conditions. Vertebrate and invertebrate gap junctions represent different structures with converging functions [5]. In mammals, five of the 21 connexin genes
Current Biology 29, R358–R380, May 20, 2019 R373
Current Biology
Dispatches A
B
Larval and adult
Dauer
14 of 25 INXs stably expressed in NS All neurons classes express INXs Most neurons express multiple INXs 98 of 118 neuron classes express unique combinations of INXs
11 of 14 INX genes modified 86 of 118 neuron classes show changes Up to 3 INXs are modified in a single neuron
1 INX expressed in only one class
eat-5, only expressed in AWA cells, is turned off inx-6 is only expressed in Dauer
C
BAG neuron CHE-7 / INX-6
AIB neuron
INX-6 / INX-6
Current Biology
Figure 2. The electrical connectome of C. elegans is plastic. (A) The cartoon summarizes the expression of innexins (INX) in the 118 neuronal classes of the nervous system of the adult C. elegans. (B) The electrical connectome is plastic. The cartoon summarizes changes in the expression of neuronal innexins observed in the dauer larva. (C) Dauer-specific expression of innexin 6 (INX-6), green in AIB neurons (grey and orange), forming homotypic channels. Heterotypic channels are also formed with the BAG neuron, which expresses the CHE-7 innexin (CHE-7, red).
have been reported to be expressed in neurons [1]. Connexins are known to play a critical role during brain development, guiding proper migration and leading to the formation of neural circuits. In the adult, the retina is the structure that exhibits the largest diversity of connexin expression and electrical synapses are known to play critical functional roles in the processing of information within retinal circuits [6]. However, in most neuron classes electrical transmission is mediated by connexin 36 (Cx36), which only forms homotypic channels, dramatically reducing the possibility of diversity of electrical synapses based on the co-existence of multiple connexins. Interestingly, two Cx36-related genes, Cx35 and Cx34, are present in fish, amphibia and birds [7–9]. The proteins encoded by these genes are capable of
forming heterotypic channels, a configuration that was shown to provide a mechanism for functional asymmetry [10]. Also, these two connexins were shown to be co-expressed in the same cell but targeted to different cellular compartments [11]. While it is unclear why Cx34 was lost in mammals and Cx35 (the ortholog of Cx36) conserved, diversity of electrical synapse based on the expression of multiple connexins can thus also occur at connexin-based electrical synapses. The value of such diversity is further emphasized by teleost fish, which constitute 50% of all vertebrate species and underwent a more recent genome duplication and therefore contain two orthologs of the Cx35 and Cx34 genes [7], thus increasing the number of combinatorial possibilities for heterotypic channels. Finally, rather than simple
R374 Current Biology 29, R358–R380, May 20, 2019
aggregates of channels, electrical synapses are currently considered complex synaptic structures that include a multiplicity of scaffolding and regulatory molecules which are required for normal synaptic function [12]. Diversity of electrical synapses can arise from differences in the presence and/or distribution of these associated proteins at each side of the junction. Consistent with this possibility, two connexinassociated proteins have been reported to be required on the postsynaptic side of mixed synapses in fish [13,14]. Differences in scaffolding and associated proteins could constitute a source of diversity at electrical synapses containing homotypic channels, such as those formed by Cx36. The spanish poet Blas de Otero once wrote, ‘‘reality amazes me, more for its silence than for the sounds it brings’’ [15]. Similarly, the findings of Bhattacharya et al. raise an infinite set of fascinating questions, such as, what do different innexins provide functionally? How are different innexins shipped to different compartments of the same neuron? Which proteins are associated with electrical synapses in invertebrates and how is the cell-specific expression of these innexins regulated to create synaptic diversity? The description of the electrical connectome in C. elegans provides a preview of future studies of the functional diversity of electrical synapses and its underlying molecular determinants, which will be facilitated by the unparalleled amenability of this organism to genetic and cellular analysis, in combination with recently available functional approaches [16].
REFERENCES 1. Beyer, E.C., and Berthoud, V.M. (2018). Gap junction gene and protein families: connexins, innexins, and pannexins. Biochim. Biophys. Acta - Biomembr. 1860, 5–8. 2. Palacios-Prado, N., Huetteroth, W., and Pereda, A.E. (2014). Hemichannel composition and electrical synaptic transmission: molecular diversity and its implications for electrical rectification. Front. Cell. Neurosci. 8, 324. 3. Bhattacharya, A., Aghayeva, U., Berghoff, E.G., and Hobert, O. (2019). Plasticity of the electrical connectome of C. elegans. Cell 176, 1174–1189.
Current Biology
Dispatches the gap and beyond. Dev. Neurobiol. 77, 562–574.
4. Bargmann, C.I., and Marder, E. (2013). From the connectome to brain function. Nat. Methods 10, 483–490.
the perch retina define a distinct subgroup of the connexin family. J. Neurosci. 18, 7625– 7637.
5. Pereda, A.E., and Macagno, E. (2017). Electrical transmission: two structures, same functions? Dev. Neurobiol. 77, 517–552.
9. Abascal, F., and Zardoya, R. (2013). Evolutionary analyses of gap junction protein families. Biochim. Biophys. Acta 1828, 4–14.
13. Miller, A.C., Voelker, L.H., Shah, A.N., and Moens, C.B. (2015). Neurobeachin is required postsynaptically for electrical and chemical synapse formation. Curr. Biol. 25, 16–28.
6. Bloomfield, S.A., and Vo¨lgyi, B. (2009). The diverse functional roles and regulation of neuronal gap junctions in the retina. Nat. Rev. Neurosci. 10, 495–506.
10. Rash, J.E., Curti, S., Vanderpool, K.G., Kamasawa, N., Nannapaneni, S., PalaciosPrado, N., Flores, C.E., Yasumura, T., O’Brien, J., Lynn, B.D., et al. (2013). Molecular and functional asymmetry at a vertebrate electrical synapse. Neuron 79, 957–969.
14. Marsh, A.J., Michel, J.C., Adke, A.P., Heckman, E.L., and Miller, A.C. (2017). Asymmetry of an intracellular scaffold at vertebrate electrical synapses. Curr. Biol. 27, 3561–3567.
7. Miller, A.C., Whitebirch, A.C., Shah, A.N., Marsden, K.C., Granato, M., O’Brien, J., and Moens, C.B. (2017). A genetic basis for molecular asymmetry at vertebrate electrical synapses. Elife 6, e25364. 8. O’Brien, J., Bruzzone, R., White, T.W., AlUbaidi, M.R., and Ripps, H. (1998). Cloning and expression of two related connexins from
11. O’Brien, J., Nguyen, H.B., and Mills, S.L. (2004). Cone photoreceptors in bass retina use two connexins to mediate electrical coupling. J. Neurosci. 24, 5632–5642. 12. Miller, A.C., and Pereda, A.E. (2017). The electrical synapse: Molecular complexities at
15. Otero, B. de (1980). Historias fingidas y verdaderas (Alianza Editorial). 16. Wu, L., Dong, A., Dong, L., Wang, S.-Q., and Li, Y. (2019). PARIS, an optogenetic method for functionally mapping gap junctions. Elife 8, e43366.
Organelle Contact Sites: Lipid Droplets Hooked by Metabolically Controlled Tethers Maria Bohnert1,2 1Institute
of Cell Dynamics and Imaging, University of Mu¨nster, Von-Esmarch-Str. 56, 48149 Mu¨nster, Germany Cluster of Excellence (EXC 1003 – CiM), University of Mu¨nster, Germany Correspondence: [email protected] https://doi.org/10.1016/j.cub.2019.03.049 2Cells-in-Motion
Lipid droplets are physically linked to other organelles via contact sites for communication, but the underlying molecular machineries are poorly characterized. Recent studies identify metabolically controlled sorting nexin tether proteins as important players at these sites.
Contact sites are unique niches in the cell in which different organelles are actively positioned at close proximity, just a few nanometers apart [1]. These sites act as hubs for interorganellar communication and mediate diverse functions, including lipid and metabolite transport, organelle positioning and distribution, membrane dynamics, and many more. In recent years, it has become apparent that most, if not all, organelles form contact sites with one another. The formation and function of these structures depends on proteinaceous contact-site machineries. Their key constituents are proteins termed ‘tethers’, which directly bridge the surfaces of different organelles and thus form the molecular basis for their communication [2].
Lipid droplets (LDs) are ubiquitous organelles that are derived from the endoplasmic reticulum (ER). LDs have a central role in cellular fat storage, are actively involved in diverse routes of lipid metabolism, and fulfill roles beyond lipid handling [3]. Like other organelles, LDs have been found to form contact sites [4,5], and their most prominent contact is with the ER, reflecting the tight links of these organelles with respect to lipid metabolism and LD biogenesis. LDs are formed via the synthesis of neutral lipids that accumulate between the leaflets of the ER membrane and ultimately bud towards the cytosol. Mature LDs thus have a unique architecture, consisting of a neutral lipid core covered by a phospholipid monolayer derived from the outer leaflet of the ER membrane [6,7]. Lipidic continuities at LD–ER contact
sites have been observed, and these may be linked to the LD biogenesis process or play a role in organelle communication. Possibly due to the special architecture and physical properties of LDs, our molecular understanding of LD contacts is lagging behind that of other organelle contact sites, and it had proven particularly hard to identify proteins involved in LD contact site formation and function and to pinpoint their exact molecular roles [4]. However, two recent papers from Mike Henne’s lab [8,9] now describe the homologous sorting nexin proteins Snx14 (from humans) and Mdm1 (from yeast) as key players in LD contact site formation (Figure 1). Both proteins mark LD contact sites and are involved in LD biogenesis from the ER in response to specific metabolic stimuli.
Current Biology 29, R358–R380, May 20, 2019 ª 2019 Elsevier Ltd. R375
Dispatches regardless of where in the forest the male- and female-skewed populations were located. Finally, manipulating adult sex ratios in large populations of mobile organisms such as birds seems perilous, as the animals are likely to disperse and balance out the targeted local sex ratio biases. To some extent, this was the case for female-skewed plots (where females dispersed from them and consequently the adult sex ratio became close to even; Figure 2), but male brown-headed nuthatches did not disperse far, leading to heavily maleskewed plots. Intriguingly, the presence of surplus males had a self-reinforcing effect: male offspring that hatched in the maleskewed plots were more likely to stay, and, surprisingly, male-skewed plots appeared to attract males from the outside. The result not only provides the key information that mate shortage leads to postponed independent breeding but also raises intriguing new questions: how do animals perceive skewed adult sex ratios? Do young
individuals use social information to help them decide whether to stay as subordinate in a group or disperse and became an independent breeder? The presence of surplus males may attract more males because in natural settings it would reflect a high-quality habitat. As nuthatch helpers are often unrelated to the family they join, the direct benefits of helping, such as access to food and mates and to a potential territory in the future, may thus be important drivers for individuals to stay and help. Therefore, Cox and colleagues [4] made a major step towards uncovering the role of a demographic trait (adult sex ratio) in a puzzling social behaviour (cooperative breeding), and their results open an exciting avenue for future research into how social information affects breeding systems.
2. Darwin, C. (1859). On the Origin of Species by Means of Natural Selection (London: Murray). 3. Cockburn, A. (1998). Evolution of helping behavior in cooperatively breeding birds. Annu. Rev. Ecol. Syst. 29, 141–177. 4. Cox, J.A., Cusick, J.A., and DuVal, E.H. (2019). Manipulated sex ratios alter group structure and cooperation in the brown-headed nuthatch. Behav. Ecol. https://doi.org/10.1093/beheco/ arz030. kely, T., Bessinger, S., and 5. Jennions, M., Sze Kappeler, P.M. (2017). Sex ratios. Curr. Biol. 27, R790–R792. kely, T., Weissing, F.J., and Komdeur, J. 6. Sze (2014). Adult sex ratio variation: implications for breeding system evolution. J. Evol. Biol. 27, 1500–1512. kely, T., and 7. Schacht, R., Kramer, K.L., Sze Kappeler, P.M. (2017). Adult sex ratios and reproductive decisions: a critical reexamination of sex differences in human and animal societies. Philos. Trans. R. Soc. B 372, 20160309.
REFERENCES
kely, T., Long, X., and Kingma, 8. Komdeur, J., Sze S.A. (2017). Adult sex ratios and the implications for cooperative breeding in birds. Philos. Trans. R. Soc. B 372, 20160322.
1. Koenig, W.D., and Dickinson, J. (2016). Cooperative Breeding in Vertebrates: Studies of Ecology, Evolution and Behavior (Cambridge: Cambridge University Press).
kely, T. 9. Liker, A., Freckleton, R.P., and Sze (2013). The evolution of sex roles in birds is related to adult sex ratio. Nat. Commun. 4, 1587.
Neuroscience: The Hidden Diversity of Electrical Synapses Alberto E. Pereda Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA Correspondence: [email protected] https://doi.org/10.1016/j.cub.2019.04.002
The complete description of the expression of gap junction proteins in the nervous system of the worm reveals a great complexity of their distribution amongst different neuronal classes, opening an unprecedented opportunity to expose the functional diversity of electrical synapses. Interconnected neurons communicate with each other at structures named synapses, where information is mediated via either the release of a transmitter substance (‘chemical synapses’) or the spread of electrical currents at a direct communicating pathway formed by aggregates of intercellular channels known as ‘gap junctions’ (‘electrical synapses’), a prevalent form of signaling in neurons (Figure 1A). Chemical
synapses are known to be functionally diverse by combining different modalities of release, neurotransmitters and receptors. In contrast, the diversity of electrical synapses is less known. A potential mechanism for diversity in electrical synapses lies in the identity of the gap junction channel-forming proteins, named ‘connexins’ and ‘innexins’ in vertebrates and invertebrates, respectively [1]. Since the
R372 Current Biology 29, R358–R380, May 20, 2019 ª 2019 Elsevier Ltd.
intercellular channel is formed by the docking of two channels, or ‘hemichannels’, each provided by one of the contacting cells, it is possible to have intercellular channels made by hemichannels formed by a single protein (homotypic intercellular channel), two different proteins (heterotypic intercellular channel) or by heteromeric channels in either homotypic or heterotypic configurations (Figure 1B) [2].
Current Biology
Dispatches A report by Bhattacharya et al. that recently appeared in the journal Cell [3] provides a full description of the expression pattern of innexins in the neurons of the worm Caenorhabditis elegans nervous system, thus exposing the distribution of electrical synapses, or ‘electrical connectome’, of this model organism. The work represents an authentic tour de force and the first full description of an electrical connectome of any nervous system. The report shows that 14 of the 25 C. elegans innexin genes are expressed in neurons and that all of the 118 neuron classes of this worm express innexins. Interestingly, most neurons express multiple innexins and more than 30 neurons express at least 10 innexins (maximum 11) (Figure 2A). In contrast, one innexin (eat-5) is expressed in only one neuron class. Remarkably, 98 of the 118 neuron classes expressed unique combinations of innexins. With a few exceptions, this distribution was found to be stable in larval stages and the adult worm, suggesting that different innexins or channels formed by combinations of them are capable of providing diversity of electrical communication within this nervous system. The full extent of the functional differences brought by different innexins remains to be determined. We know, for example, that heterotypic gap junction channels are generally associated with rectification (preferential current flow in one direction) of electrical transmission [2]. In addition to the exhaustive description of the electrical connectome, the study also provides evidence that the wiring formed by the expression of these proteins is plastic, that is, it can under some circumstances be modified. Under challenging envirommental conditions C. elegans larvae undergo an arrest (a type of stasis or period of inactvity) named dauer, during which the larvae can survive harsh conditions. The study found that 11 of the 14 innexins were modified (their expression increased or decreased) and these changes were observed in 86 of the 118 neuron classes (Figure 2B). Some changes were specific: eat-5 was exclusively reduced in the AWA cell and, strikingly, inx-6 was expressed in AIB cells only in the dauer state. The dauer-specific expression of
A Gap junction Neuron 1
Neuron 2
Heteromeric heterotypic
Homotypic
B
Cell 1 Cell 2
Heterotypic
Heteromeric homotypic Current Biology
Figure 1. Gap junctions mediate synaptic transmission between neurons. (A) Gap junctions (Gap junction, blue) are aggregates of intercellular channels formed by the docking of two ‘hemichannels’, each contributed by one of the connected cells. Gap junctions allow electrical and chemical synaptic communication between two adjacent cells (arrows). (B) Intercellular channels might exist in different configurations. The cartoon summarizes the possible configurations formed by two different channel forming proteins (vertebrate connexins or invertebrate innexins) represented here by red and green colors (Cell 1 and Cell 2 indicate the membrane of each cell).
inx-6 (innexin 6, INX-6) provided the opportunity to examine in detail the state-dependent changes as well as to expose the molecular triggers of these changes. In an elegant set of experiments demonstrating the utility of C. elegans for exploring mechanistic insights, the study finds that INX-6 forms dauer-specific homotypic gap junctions between the right and the left AIB cells and heterotypic channels with the BAG cell, which instead expresses the CHE-7 innexin (Figure 2C). In other words, two different types of electrical synapses are formed by AIB cells during this stage. Furthermore, this rewiring was linked to the altered locomotor and chemosensory behaviors of the dauer larva. Finally, the authors identified the gene regulatory mechanism mediating the dauer-specific expression of inx-6, involving terminal selector and FoxO transcription factors. Thus, the expression of specific innexins is capable of providing functional differences, further suggesting that the
diversity of innexin proteins likely constitutes a source of functional diversity for electrical synapses. The description of the connectome of a given nervous system is arguably necessary but not sufficient to understand the behavior of neural networks, a catalog of possible connections of overlapping networks of chemical and electrical synapses whose functional states can be regulated by neurotransmitter modulators to reconfigure circuits [4]. The study by Bhattacharya et al. [3] shows that hardwired connectomes are, under certain conditions, also modifiable. It is presently unclear if this remodeling of the connectome is only due to the extreme conditions of the dauer larva or can also occur, perhaps to a lesser extent, under normal physiological conditions. Vertebrate and invertebrate gap junctions represent different structures with converging functions [5]. In mammals, five of the 21 connexin genes
Current Biology 29, R358–R380, May 20, 2019 R373
Current Biology
Dispatches A
B
Larval and adult
Dauer
14 of 25 INXs stably expressed in NS All neurons classes express INXs Most neurons express multiple INXs 98 of 118 neuron classes express unique combinations of INXs
11 of 14 INX genes modified 86 of 118 neuron classes show changes Up to 3 INXs are modified in a single neuron
1 INX expressed in only one class
eat-5, only expressed in AWA cells, is turned off inx-6 is only expressed in Dauer
C
BAG neuron CHE-7 / INX-6
AIB neuron
INX-6 / INX-6
Current Biology
Figure 2. The electrical connectome of C. elegans is plastic. (A) The cartoon summarizes the expression of innexins (INX) in the 118 neuronal classes of the nervous system of the adult C. elegans. (B) The electrical connectome is plastic. The cartoon summarizes changes in the expression of neuronal innexins observed in the dauer larva. (C) Dauer-specific expression of innexin 6 (INX-6), green in AIB neurons (grey and orange), forming homotypic channels. Heterotypic channels are also formed with the BAG neuron, which expresses the CHE-7 innexin (CHE-7, red).
have been reported to be expressed in neurons [1]. Connexins are known to play a critical role during brain development, guiding proper migration and leading to the formation of neural circuits. In the adult, the retina is the structure that exhibits the largest diversity of connexin expression and electrical synapses are known to play critical functional roles in the processing of information within retinal circuits [6]. However, in most neuron classes electrical transmission is mediated by connexin 36 (Cx36), which only forms homotypic channels, dramatically reducing the possibility of diversity of electrical synapses based on the co-existence of multiple connexins. Interestingly, two Cx36-related genes, Cx35 and Cx34, are present in fish, amphibia and birds [7–9]. The proteins encoded by these genes are capable of
forming heterotypic channels, a configuration that was shown to provide a mechanism for functional asymmetry [10]. Also, these two connexins were shown to be co-expressed in the same cell but targeted to different cellular compartments [11]. While it is unclear why Cx34 was lost in mammals and Cx35 (the ortholog of Cx36) conserved, diversity of electrical synapse based on the expression of multiple connexins can thus also occur at connexin-based electrical synapses. The value of such diversity is further emphasized by teleost fish, which constitute 50% of all vertebrate species and underwent a more recent genome duplication and therefore contain two orthologs of the Cx35 and Cx34 genes [7], thus increasing the number of combinatorial possibilities for heterotypic channels. Finally, rather than simple
R374 Current Biology 29, R358–R380, May 20, 2019
aggregates of channels, electrical synapses are currently considered complex synaptic structures that include a multiplicity of scaffolding and regulatory molecules which are required for normal synaptic function [12]. Diversity of electrical synapses can arise from differences in the presence and/or distribution of these associated proteins at each side of the junction. Consistent with this possibility, two connexinassociated proteins have been reported to be required on the postsynaptic side of mixed synapses in fish [13,14]. Differences in scaffolding and associated proteins could constitute a source of diversity at electrical synapses containing homotypic channels, such as those formed by Cx36. The spanish poet Blas de Otero once wrote, ‘‘reality amazes me, more for its silence than for the sounds it brings’’ [15]. Similarly, the findings of Bhattacharya et al. raise an infinite set of fascinating questions, such as, what do different innexins provide functionally? How are different innexins shipped to different compartments of the same neuron? Which proteins are associated with electrical synapses in invertebrates and how is the cell-specific expression of these innexins regulated to create synaptic diversity? The description of the electrical connectome in C. elegans provides a preview of future studies of the functional diversity of electrical synapses and its underlying molecular determinants, which will be facilitated by the unparalleled amenability of this organism to genetic and cellular analysis, in combination with recently available functional approaches [16].
REFERENCES 1. Beyer, E.C., and Berthoud, V.M. (2018). Gap junction gene and protein families: connexins, innexins, and pannexins. Biochim. Biophys. Acta - Biomembr. 1860, 5–8. 2. Palacios-Prado, N., Huetteroth, W., and Pereda, A.E. (2014). Hemichannel composition and electrical synaptic transmission: molecular diversity and its implications for electrical rectification. Front. Cell. Neurosci. 8, 324. 3. Bhattacharya, A., Aghayeva, U., Berghoff, E.G., and Hobert, O. (2019). Plasticity of the electrical connectome of C. elegans. Cell 176, 1174–1189.
Current Biology
Dispatches the gap and beyond. Dev. Neurobiol. 77, 562–574.
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Organelle Contact Sites: Lipid Droplets Hooked by Metabolically Controlled Tethers Maria Bohnert1,2 1Institute
of Cell Dynamics and Imaging, University of Mu¨nster, Von-Esmarch-Str. 56, 48149 Mu¨nster, Germany Cluster of Excellence (EXC 1003 – CiM), University of Mu¨nster, Germany Correspondence: [email protected] https://doi.org/10.1016/j.cub.2019.03.049 2Cells-in-Motion
Lipid droplets are physically linked to other organelles via contact sites for communication, but the underlying molecular machineries are poorly characterized. Recent studies identify metabolically controlled sorting nexin tether proteins as important players at these sites.
Contact sites are unique niches in the cell in which different organelles are actively positioned at close proximity, just a few nanometers apart [1]. These sites act as hubs for interorganellar communication and mediate diverse functions, including lipid and metabolite transport, organelle positioning and distribution, membrane dynamics, and many more. In recent years, it has become apparent that most, if not all, organelles form contact sites with one another. The formation and function of these structures depends on proteinaceous contact-site machineries. Their key constituents are proteins termed ‘tethers’, which directly bridge the surfaces of different organelles and thus form the molecular basis for their communication [2].
Lipid droplets (LDs) are ubiquitous organelles that are derived from the endoplasmic reticulum (ER). LDs have a central role in cellular fat storage, are actively involved in diverse routes of lipid metabolism, and fulfill roles beyond lipid handling [3]. Like other organelles, LDs have been found to form contact sites [4,5], and their most prominent contact is with the ER, reflecting the tight links of these organelles with respect to lipid metabolism and LD biogenesis. LDs are formed via the synthesis of neutral lipids that accumulate between the leaflets of the ER membrane and ultimately bud towards the cytosol. Mature LDs thus have a unique architecture, consisting of a neutral lipid core covered by a phospholipid monolayer derived from the outer leaflet of the ER membrane [6,7]. Lipidic continuities at LD–ER contact
sites have been observed, and these may be linked to the LD biogenesis process or play a role in organelle communication. Possibly due to the special architecture and physical properties of LDs, our molecular understanding of LD contacts is lagging behind that of other organelle contact sites, and it had proven particularly hard to identify proteins involved in LD contact site formation and function and to pinpoint their exact molecular roles [4]. However, two recent papers from Mike Henne’s lab [8,9] now describe the homologous sorting nexin proteins Snx14 (from humans) and Mdm1 (from yeast) as key players in LD contact site formation (Figure 1). Both proteins mark LD contact sites and are involved in LD biogenesis from the ER in response to specific metabolic stimuli.
Current Biology 29, R358–R380, May 20, 2019 ª 2019 Elsevier Ltd. R375