Numb can antagonize Notch signaling to diversify the fates of sister cells. We report here that paired sister cells acquire different fates in all three Drosophila neuronal lineages that make diverse types of antennal lobe projection neurons (PNs). Only one in each pair of postmitotic neurons survives into the adult stage in both anterodorsal (ad) and ventral (v) PN lineages. Notably, Notch signaling specifies the PN fate in the vPN lineage but promotes programmed cell death in the missing siblings in the adPN lineage. In addition, Notch/Numb-mediated binary sibling fates underlie the production of PNs and local interneurons from common precursors in the lAL lineage. Furthermore, Numb is needed in the lateral but not adPN or vPN lineages to prevent the appearance of ectopic neuroblasts and to ensure proper self-renewal of neural progenitors. These lineage-specific outputs of Notch/Numb signaling show that a universal mechanism of binary fate decision can be utilized to govern diverse neural sibling differentiations.

The endomembrane system of eukaryotic cells uses membrane-enclosed carriers to move diverse macromolecules among different membrane-bound compartments, a requirement for cells to secrete and take up molecules from their environment. Two recycling pathways-biosynthetic and endocytic, each with specific lipid components-make up this system, with the Golgi apparatus mediating transport between the two. Here, we integrate lipid-based mechanisms into the description of this system. A partitioning model of the Golgi apparatus is discussed as a working hypothesis to explain how membrane lipids and proteins that are segregated based on lateral lipid partitioning support the unique composition of the biosynthetic and endocytic recycling pathways in the face of constant trafficking of molecular constituents. We further discuss how computational modeling can allow for interpretation of experimental findings and provide mechanistic insight into these important cellular pathways.

Michael Akam has been awarded the 2007 Kowalevsky medal for his many research accomplishments in the area of evolutionary developmental biology. We highlight three tributaries of Michaels contribution to evolutionary developmental biology. First, he has made major contributions to our understanding of development of the fruit fly, Drosophila melanogaster. Second, he has maintained a consistent focus on several key problems in evolutionary developmental biology, including the evolving role of Hox genes in arthropods and, more recently, the evolution of segmentation mechanisms. Third, Michael has written a series of influential reviews that have integrated progress in developmental biology into an evolutionary perspective. Michael has also made a large impact on the field through his effective mentorship style, his selfless promotion of younger colleagues, and his leadership of the University Museum of Zoology at Cambridge and the European community of evolutionary developmental biologists.

Although nervous system sexual dimorphisms are known in many species, relatively little is understood about the molecular mechanisms generating these dimorphisms. Recent findings in Drosophila provide the tools for dissecting how neurogenesis and neuronal differentiation are modulated by the Drosophila sex-determination regulatory genes to produce nervous system sexual dimorphisms. Here we report studies aimed at illuminating the basis of the sexual dimorphic axonal projection patterns of foreleg gustatory receptor neurons (GRNs): only in males do GRN axons project across the midline of the ventral nerve cord. We show that the sex determination genes fruitless (fru) and doublesex (dsx) both contribute to establishing this sexual dimorphism. Male-specific Fru (Fru(M)) acts in foreleg GRNs to promote midline crossing by their axons, whereas midline crossing is repressed in females by female-specific Dsx (Dsx(F)). In addition, midline crossing by these neurons might be promoted in males by male-specific Dsx (Dsx(M)). Finally, we (1) demonstrate that the roundabout (robo) paralogs also regulate midline crossing by these neurons, and (2) provide evidence that Fru(M) exerts its effect on midline crossing by directly or indirectly regulating Robo signaling.

Starvation-induced autophagosomes engulf cytosol and/or organelles and deliver them to lysosomes for degradation, thereby resupplying depleted nutrients. Despite advances in understanding the molecular basis of this process, the membrane origin of autophagosomes remains unclear. Here, we demonstrate that, in starved cells, the outer membrane of mitochondria participates in autophagosome biogenesis. The early autophagosomal marker, Atg5, transiently localizes to punctae on mitochondria, followed by the late autophagosomal marker, LC3. The tail-anchor of an outer mitochondrial membrane protein also labels autophagosomes and is sufficient to deliver another outer mitochondrial membrane protein, Fis1, to autophagosomes. The fluorescent lipid NBD-PS (converted to NBD-phosphotidylethanolamine in mitochondria) transfers from mitochondria to autophagosomes. Photobleaching reveals membranes of mitochondria and autophagosomes are transiently shared. Disruption of mitochondria/ER connections by mitofusin2 depletion dramatically impairs starvation-induced autophagy. Mitochondria thus play a central role in starvation-induced autophagy, contributing membrane to autophagosomes.

The representation of acoustic stimuli in the brainstem forms the basis for higher auditory processing. While some characteristics of this representation (e.g. tuning curve) are widely accepted, it remains a challenge to predict the firing rate at high temporal resolution in response to complex stimuli. In this study we explore models for in vivo, single cell responses in the medial nucleus of the trapezoid body (MNTB) under complex sound stimulation. We estimate a family of models, the multilinear models, encompassing the classical spectrotemporal receptive field and allowing arbitrary input-nonlinearities and certain multiplicative interactions between sound energy and its short-term auditory context. We compare these to models of more traditional type, and also evaluate their performance under various stimulus representations. Using the context model, 75% of the explainable variance could be predicted based on a cochlear-like, gamma-tone stimulus representation. The presence of multiplicative contextual interactions strongly reduces certain inhibitory/suppressive regions of the linear kernels, suggesting an underlying nonlinear mechanism, e.g. cochlear or synaptic suppression, as the source of the suppression in MNTB neuronal responses. In conclusion, the context model provides a rich and still interpretable extension over many previous phenomenological models for modeling responses in the auditory brainstem at submillisecond resolution.

The internal workings of the nucleus remain a mystery. A list of component parts exists, and in many cases their functional roles are known for events such as transcription, RNA processing, or nuclear export. Some of these components exhibit structural features in the nucleus, regions of concentration or bodies that have given rise to the concept of functional compartmentalization–that there are underlying organizational principles to be described. In contrast, a picture is emerging in which transcription appears to drive the assembly of the functional components required for gene expression, drawing from pools of excess factors. Unifying this seemingly dual nature requires a more rigorous approach, one in which components are tracked in time and space and correlated with onset of specific nuclear functions. In this chapter, we anticipate tools that will address these questions and provide the missing kinetics of nuclear function. These tools are based on analyzing the fluctuations inherent in the weak signals of endogenous nuclear processes and determining values for them. In this way, it will be possible eventually to provide a computational model describing the functional relationships of essential components.

A striking aspect of cortical neural networks is the divergence of a relatively small number of input channels from the peripheral sensory apparatus into a large number of cortical neurons, an over-complete representation strategy. Cortical neurons are then connected by a sparse network of lateral synapses. Here we propose that such architecture may increase the persistence of the representation of an incoming stimulus, or a percept. We demonstrate that for a family of networks in which the receptive field of each neuron is re-expressed by its outgoing connections, a represented percept can remain constant despite changing activity. We term this choice of connectivity REceptive FIeld REcombination (REFIRE) networks. The sparse REFIRE network may serve as a high-dimensional integrator and a biologically plausible model of the local cortical circuit.

Recently it was demonstrated that long-lived quantum coherence exists during excitation energy transport in photosynthesis. It is a valid question up to which length, time and mass scales quantum coherence may extend, how one may detect this coherence and what, if any, role it plays in the dynamics of the system. Here we suggest that the selectivity filter of ion channels may exhibit quantum coherence, which might be relevant for the process of ion selectivity and conduction. We show that quantum resonances could provide an alternative approach to ultrafast two-dimensional (2D) spectroscopy to probe these quantum coherences. We demonstrate that the emergence of resonances in the conduction of ion channels that are modulated periodically by time-dependent external electric fields can serve as signatures of quantum coherence in such a system. Assessments of experimental feasibility and specific paths towards the experimental realization of such experiments are presented.

According to spike-timing-dependent plasticity (STDP), the timing of the Na(+) spike relative to the EPSP determines whether LTP or LTD will occur. Here, we review our reservations about STDP. Most investigations of this process have been done under conditions in which the spike is evoked by postsynaptic current injection. Under more realistic conditions, in which the spike is evoked by the EPSP, the results do not generally support STDP. For instance, low-frequency stimulation of a group of synapses can cause LTD, not the LTP predicted by the pre-before-post sequence in STDP; this is true regardless of whether or not the EPSP is large enough to produce a Na(+) spike. With stronger or more frequent stimulation, LTP can be induced by the same pre-before-post timing, but in this case block of Na(+) spikes does not necessarily prevent LTP induction. Thus, Na(+) spikes may facilitate LTP and/or LTD under some conditions, but they are not necessary, a finding consistent with their small size relative to the EPSP in many parts of pyramidal cell dendrites. The nature of the dendritic depolarizing events that control bidirectional plasticity is of central importance to understanding neural function. There are several candidates, including backpropagating action potentials, but also dendritic Ca(2+) spikes, the AMPA receptor-mediated EPSP, and NMDA receptor-mediated EPSPs or spikes. These often appear to be more important than the Na(+) spike in providing the depolarization necessary for plasticity. We thus feel that it is premature to accept STDP-like processes as the major determinant of LTP/LTD.