Integration of receptor tyrosine kinase, integrin, and cadherin activities is crucial for normal cell growth, motility, and adhesion. Here, we describe roles for p120-catenin (p120) and p190RhoGAP that coordinate crosstalk between these systems and regulate cadherin function. Surprisingly, PDGFR-induced actin remodeling in NIH3T3 cells is blocked in the absence of p120, and the cells are partially transformed via constitutive activation of Rho. We have traced the mechanism to unexpected codependent roles for p120 and p190RhoGAP in regulating Rac-dependent antagonism of Rho. Receptor-induced Rac activity causes translocation of p190RhoGAP to adherens junctions (AJs), where it couples to the cadherin complex via interaction with p120. AJ formation is dependent on this p120-p190RhoGAP interaction and fails altogether if either of these proteins are compromised. We propose that Rac activation links diverse signaling systems to AJ assembly by controlling transient p190RhoGAP interactions with p120 and localized inhibition of Rho.

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Highlights d Relative to mouse counterparts, primate connections are sparse d Primate excitatory neurons receive fewer excitatory and inhibitory inputs d Primate inhibitory neurons have fewer somatic inputs but equivalent shaft inputs d Across species, inhibitory axons have similar innervation properties

Dopaminergic (DA) neurons exert profound influences on behavior including addiction. However, how DA axons communicate with target neurons and how those communications change with drug exposure remains poorly understood. We leverage cell type-specific labeling with large volume serial electron microscopy to detail DA connections in the nucleus accumbens (NAc) of the mouse (Mus musculus) before and after exposure to cocaine. We find that individual DA axons contain different varicosity types based on their vesicle contents. Spatially ordering along individual axons further suggests that varicosity types are non-randomly organized. DA axon varicosities rarely make specific synapses (<2%, 6/410), but instead are more likely to form spinule-like structures (15%, 61/410) with neighboring neurons. Days after a brief exposure to cocaine, DA axons were extensively branched relative to controls, formed blind-ended ‘bulbs’ filled with mitochondria, and were surrounded by elaborated glia. Finally, mitochondrial lengths increased by ~2.2 times relative to control only in DA axons and NAc spiny dendrites after cocaine exposure. We conclude that DA axonal transmission is unlikely to be mediated via classical synapses in the NAc and that the major locus of anatomical plasticity of DA circuits after exposure to cocaine are large-scale axonal re-arrangements with correlated changes in mitochondria.

We asked how a new, complex trait evolves by selecting for diurnal oscillations in the budding yeast, Saccharomyces cerevisiae. We expressed yellow fluorescent protein (YFP) from a yeast promoter and selected for a regular alternation between low and high fluorescence over a 24-hr period. This selection produced changes in cell adhesion rather than YFP expression: clonal populations oscillated between single cells and multicellular clumps. The oscillations are not a response to environmental cues and continue for at least three cycles in a constant environment. We identified eight putative causative mutations in one clone and recreated the evolved phenotype in the ancestral strain. The mutated genes lack obvious relationships to each other, but multiple lineages change from the haploid to the diploid pattern of gene expression. We show that a novel, complex phenotype can evolve by small sets of mutations in genes whose molecular functions appear to be unrelated to each other.DOI: http://dx.doi.org/10.7554/eLife.04875.001

Purpose Dysmyelinating diseases are characterized by abnormal myelin formation and function. Such microstructural abnormalities in myelin have been demonstrated to produce measurable effects on the MR signal. This work examines these effects on measurements of voxel‐wise, high‐resolution water spectra acquired using a 3D echo‐planar spectroscopic imaging (EPSI) pulse sequence from both postmortem fixed control mouse brains and a dysmyelination mouse brain model. Methods Perfusion fixed, resected control (n = 5) and shiverer (n = 4) mouse brains were imaged using 3D‐EPSI with 100 µm isotropic resolution. The free induction decay (FID) was sampled every 2.74 ms over 192 echoes, for a total sampling duration of 526.08 ms. Voxel‐wise FIDs were Fourier transformed to produce water spectra with 1.9 Hz resolution. Spectral asymmetry was computed and compared between the two tissue types. Results The water resonance is more asymmetrically broadened in the white matter of control mouse brain compared with dysmyelinated white matter. In control brain, this is modulated by and consistent with previously reported orientationally dependent effects of white matter relative to B0. Similar sensitivity to orientation is observed in dysmyelinated white matter as well; however, the magnitude of the resonance asymmetry is much lower across all directions. Conclusion Results demonstrate that components of the spectra are specifically differentially affected by myelin concentration. This suggests that water proton spectra may be sensitive to the presence of myelin, and as such, could serve as a MRI‐based biomarker of dysmyelinating disease, free of mathematical models.

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We report that the rate of synapse development in primary sensory cortices of mice and macaques is unrelated to lifespan, as was previously thought. We analyzed 28,084 synapses over multiple developmental time points in both species and find, instead, that net excitatory synapse development of mouse and macaque neurons primarily increased at similar rates in the first few postnatal months, and then decreased over a span of 1-1.5 years of age. The development of inhibitory synapses differed qualitatively across species. In macaques, net inhibitory synapses first increase and then decrease on excitatory soma at similar ages as excitatory synapses. In mice, however, such synapses are added throughout life. These findings contradict the long-held belief that the cycle of synapse formation and pruning occurs earlier in shorter-lived animals. Instead, our results suggest more nuanced rules, with the development of different types of synapses following different timing rules or different trajectories across species.