Mitochondria are dynamic organelles, undergoing both fission and fusion regularly in interphase cells. Mitochondrial fission is thought to be part of a quality control mechanism, whereby damaged mitochondrial components are segregated from healthy components in an individual mitochondrion, followed by mitochondrial fission and degradation of the damaged daughter mitochondrion . Fission also plays a role in apoptosis . Defects in mitochondrial dynamics can lead to neurodegenerative diseases such as Alzheimer’s . Mitochondrial fission requires the dynamin GTPase Drp1, which assembles in a ring around the mitochondrion and appears to constrict both outer and inner mitochondrial membranes . However, mechanisms controlling Drp1 assembly on mammalian mitochondria are unclear. Recent results show that actin polymerization, driven by the endoplasmic reticulum-bound formin protein INF2, stimulates Drp1 assembly at fission sites . Here, we show that myosin II also plays a role in fission. Chemical inhibition by blebbistatin or siRNA-mediated suppression of myosin IIA or myosin IIB causes an increase in mitochondrial length in both control cells and cells expressing constitutively active INF2. Active myosin II accumulates in puncta on mitochondria in an actin- and INF2-dependent manner. In addition, myosin II inhibition decreases Drp1 association with mitochondria. Based on these results, we propose a mechanistic model in which INF2-mediated actin polymerization leads to myosin II recruitment and constriction at the fission site, enhancing subsequent Drp1 accumulation and fission.
Social insects are important models for social evolution and behavior. However, in many species experimental control over important factors that regulate division of labor, such as genotype and age, is limited [1, 2]. Furthermore, most species have fixed queen and worker castes, making it difficult to establish causality between the molecular mechanisms that underlie reproductive division of labor, the hallmark of insect societies . Here we present the genome of the queenless clonal raider ant Cerapachys biroi, a powerful new study system that does not suffer from these constraints. Using cytology and RAD-Seq, we show that C. biroi reproduces via automixis with central fusion and that heterozygosity is lost extremely slowly. As a consequence, nestmates are almost clonally related (r=0.996). Workers in C. biroi colonies synchronously alternate between reproduction and brood care, and young workers eclose in synchronized cohorts. We show that genes associated with division of labor in other social insects are conserved in C. biroi and dynamically regulated during the colony cycle. With unparalleled experimental control over an individual’s genotype and age, and the ability to induce reproduction and brood care [4, 5], C. biroi has great potential to illuminate the molecular regulation of division of labor.
Many bacteria glide smoothly on surfaces, but with no discernable propulsive organelles on their surface. Recent experiments with Myxococcus xanthus and Flavobacterium johnsoniae show that both distantly related bacterial species glide utilizing proteins that move in helical tracks, albeit with significantly different motility mechanisms. Both species utilize proton motive force for movement. However, the motors that power gliding in M. xanthus have been identified, while the F. johnsoniae motors remain to be discovered.
Understanding the molecular basis of phenotypic diversity is a critical challenge in biology, yet we know little about the mechanistic effects of different mutations and epistatic relationships among loci that contribute to complex traits. Pigmentation genetics offers a powerful model for identifying mutations underlying diversity, and for determining how additional complexity emerges from interactions among loci. Centuries of artificial selection in domestic rock pigeons have cultivated tremendous variation in plumage pigmentation through the combined effects of dozens of loci. The dominance and epistatic hierarchies of key loci governing this diversity are known through classical genetic studies [1-6], but their molecular identities and the mechanisms of their genetic interactions remain unknown. Here we identify protein-coding and cis-regulatory mutations in Tyrp1, Sox10, and Slc45a2 that underlie classical color phenotypes of pigeons, and present a mechanistic explanation of their dominance and epistatic relationships. We also find unanticipated allelic heterogeneity at Tyrp1 and Sox10, indicating that color variants evolved repeatedly though mutations in the same genes. These results demonstrate how a spectrum of coding and regulatory mutations in a small number of genes can interact to generate substantial phenotypic diversity in a classic Darwinian model of evolution .
Cell size control requires mechanisms that integrate cell growth and division. Key to this integration in fission yeast is the SAD family kinase Cdr2, which organizes a set of cortical nodes in the cell middle to promote mitotic entry through Wee1 and Cdk1 [1-3]. Cdr2 is inhibited by a spatial gradient of the DYRK kinase Pom1 emanating from cell tips in a cell size-dependent manner [2, 3], but how the Pom1 gradient inhibits Cdr2 activity during cell growth is unknown. Here, we show that Pom1 acts to prevent activation of Cdr2 kinase activity by the CaMKK Ssp1. We found that Ssp1 activates Cdr2 through phosphorylation of a conserved threonine residue (Thr166) in the activation loop of the Cdr2 N-terminal kinase domain both in vitro and in cells. The levels of this activating phosphorylation increased with cell cycle progression, and genetic epistasis demonstrated that Ssp1 promotes mitotic entry through Cdr2. Intriguingly, Pom1 phosophorylated the C-terminal domain (CTD) of Cdr2, and this modification reduced Cdr2-T166 phosphorylation by Ssp1. These findings show how activation of the conserved mitotic inducer Cdr2 is integrated with an inhibitory spatial gradient to ensure proper cell size control at mitosis.
The biogenesis of mitochondria requires the import of a large number of proteins from the cytosol [1, 2]. While numerous studies have defined the proteinaceous machineries that mediate mitochondrial protein sorting, little is known about the role of lipids in mitochondrial protein import. Cardiolipin, the signature phospholipid of the mitochondrial inner membrane [3–5], affects the stability of many inner membrane protein complexes [6–12]. Perturbation of cardiolipin metabolism leads to the X-linked cardioskeletal myopathy, Barth syndrome [13–18]. We report that cardiolipin affects the preprotein translocases of the mitochondrial outer membrane. Cardiolipin mutants genetically interact with mutants of outer membrane translocases. Mitochondria from cardiolipin yeast mutants, as well as Barth syndrome patients, are impaired in the biogenesis of outer membrane proteins. Our findings reveal a new role for cardiolipin in protein sorting at the mitochondrial outer membrane and bear implications for the pathogenesis of Barth syndrome.
The visual system is now known to be composed of image-forming and non-image-forming pathways. Photoreception for the image-forming pathway begins at the rods and cones, whereas that for the non-image-forming pathway also involves intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin. In the mouse retina, the rod and cone photoreceptors become light responsive from postnatal day 10 (P10); however, the development of photosensitivity of the ipRGCs remains largely unexplored.
Here, we provide direct physiological evidence that the ipRGCs are light responsive from birth (P0) and that this photosensitivity requires melanopsin expression. Interestingly, the number of ipRGCs at P0 is over five times that in the adult retina, reflecting an initial overproduction of melanopsin-expressing cells during development. Even at P0, the ipRGCs form functional connections with the suprachiasmatic nucleus, as assessed by light-induced Fos expression.
The findings suggest that the non-image-forming pathway is functional long before the mainstream image-forming pathway during development.
HAP2, a male gamete-specific protein conserved across vast evolutionary distances has garnered considerable attention as a potential membrane fusogen required for fertilization in taxa ranging from protozoa and green algae to flowering plants and invertebrate animals [1–6]. However, its presence in Tetrahymena thermophilaa ciliated protozoan with seven sexes or mating types that bypasses the production of male gametes raises interesting questions regarding the evolutionary origins of gamete-specific functions in sexually dimorphic species. Here we show that HAP2 is expressed in all seven mating types of T. thermophila and that fertility is only blocked when the gene is deleted from both cells of a mating pair. HAP2 deletion strains of complementary mating types can recognize one another and form pairs, however pair stability is compromised and membrane pore formation at the nuclear exchange junction is blocked. The absence of pore formation is consistent with previous studies suggesting a role for HAP2 in gamete fusion in other systems. We propose a model in which each of the several hundred membrane pores established at the conjugation junction of mating Tetrahymena represents the equivalent of a male/female interface, and that pore formation is driven on both sides of the junction by the presence of HAP2. Such a model supports the idea that many of the disparate functions of sperm and egg were shared by the “isogametes” of early eukaryotes, and became partitioned to either male or female sex cells later in evolution.
In ball sports, we are taught to follow through, despite the inability of events after contact or release to influence the outcome [1, 2]. Here we show that the specific motor memory active at any given moment critically depends on the movement that will be made in the near future. We demonstrate that associating a different follow-through movement with two motor skills that normally interfere [3–7] allows them to be learned simultaneously, suggesting that distinct future actions activate separate motor memories. This implies that when learning a skill, a variable follow-through would activate multiple motor memories across practice, whereas a consistent follow-through would activate a single motor memory, resulting in faster learning. We confirm this prediction and show that such follow-through effects influence adaptation over time periods associated with real-world skill learning. Overall, our results indicate that movements made in the immediate future influence the current active motor memory. This suggests that there is a critical time period both before  and after the current movement that determines motor memory activation and controls learning.
•Future movements determine which motor memory is currently active and modifiable•Skills that otherwise interfere can be learned if each has a unique follow-through•A single skill is learned faster if its follow-through is consistent•Selection of motor memories depends on both lead-in and follow-through movements
For a motor skill to be learned, its motor memory must be stored, protected from interference, and reactivated for modification during practice. Howard et al. demonstrate that future movement determines which motor memory is currently active and that a consistent follow-through constrains skill acquisition to a single memory, thereby speeding up learning.
How control of subcellular events in single cells determines morphogenesis on the scale of the tissue is largely unresolved. The stereotyped cross-midline mitoses of progenitors in the zebrafish neural keel [1–4] provide a unique experimental paradigm for defining the role and control of single cell orientation for tissue-level morphogenesis in vivo.
We show that the coordinated orientation of individual progenitor cell division in the neural keel is the cellular determinant required for morphogenesis into a neural tube epithelium with a single straight lumen. We find that Scribble is required for oriented cell division and that its function in this process is independent of canonical apico-basal and planar polarity pathways. We identify a role for Scribble in controlling clustering of α-Catenin foci in dividing progenitors. Loss of either Scrib or of N-cadherin results in abnormally oriented mitoses, reduced cross-midline cell divisions and similar neural tube defects. We propose that Scribble-dependent nascent cell-cell adhesion clusters between neuroepithelial progenitors contribute to define orientation of their cell division. Finally, our data demonstrate that while oriented mitoses of individual cells determine neural tube architecture, the tissue can in turn feed back on its constituent cells to define their polarization and cell division orientation to ensure robust tissue morphogenesis.
Animals with habitats in the intertidal zone often display biological rhythms that coordinate with both the tidal and the daily environmental cycles. Two recent studies show that the molecular components of the biological clocks mediating tidal rhythms are likely different from the phylogenetically conserved components that mediate circadian (daily) rhythms.
In the last stage of the C. elegans equivalent of epiboly, an open pocket in the epidermis is closed by marginal epidermal P/pocket cells that express and require VAB-1/Eph and PLX-2/plexin receptors for migration toward and alignment with contralateral partners at the ventral midline. Cellular mechanisms affected by these signaling proteins remain unknown.
A cellular bridge comprising four neuron cell bodies that spans the open pocket serves as a substratum for migration of contra-lateral P cell pair P9/10 to the midline which can facilitate similar migration of neighboring P cells. This bridge is formed by a stereotypical rearrangement of five sister pairs of PLX-2 and VAB-1 expressing cells, of which three pairs serve as a scaffold for bridge assembly and two pairs form the bridge. Bridge formation requires VAB-1 kinase-dependent extension of presumptive bridge cell protrusions toward the ventral midline. An unassembled mutant bridge obstructs but does not block P cell progression toward the midline, however, cell type-specific rescue experiments show that VAB-1 or a nearly complete cytoplasmic deletion of VAB-1 expressed by scaffold and bridge cells or by P9/10 can facilitate P cell progression to the midline. MAB-20/semaphorin and VAB-1 also exhibit complex redundancies to regulate adhesion and prevent gaps between sister bridge and scaffold forming cells that would otherwise completely block P cell migration.
The Eph receptor functions to mediate cell extensions required for bridge formation, independently facilitates P cell migration to the ventral midline, and acts redundantly with PLX-2/plexin to prevent gaps between sister plexin band cells that normally serve as a substratum for P9/10 cell migration.
semaphorin; Eph receptor; plexin; ventral enclosure; cell migration; morphogenesis