Our Mission
The goal of the Mosca Lab is to provide an environment where science of the highest calibre can be done.
Every member has the right to speak freely and be judged on the quality of their work and their character.
We commit to training students, postdocs, and technicians so they can succeed in any scientific careers.
We are a safe space that values tolerance, collaboration, truth, and support in the pursuit of outstanding science.
The Mosca Lab studies, broadly, how synapse organization arises in the brain and how that organization enables behavior. We study the Drosophila olfactory system, taking in vivo genetic, biochemical, and microscopy approaches to understand the molecular pathways that enable synapses to form and achieve the precise three-dimensional patterns seen in adults (Mosca and Luo, eLife, 2014). We also study how altering synapse organization affects the ability of the fly to smell and respond to attractive and aversive odorants. By connecting molecules with behaviors, we hope to achieve a better understanding of how synaptic organization arises to enable robust behavior.
Cell-Type Specific Synapse Organization
We study how synapses are organized in mature sensory circuits in Drosophila melanogaster. Specifically, we focus on the antennal lobe, the first order processing center for olfactory information, and akin to the human olfactory bulb. We pioneered techniques (Mosca and Luo, eLife, 2014) for studying the three-dimensional organization of synapses in the genetically identified neurons like olfactory receptor neurons (right). Recent work identified the developmental maps and mechanisms for central olfactory circuits (Aimino et al. Journal of Neuroscience, 2023) and built new postsynaptic tools (Parisi et al., Cell Reports Methods, 2023) to map circuit organization. Our current work involves using these techniques to map three-dimensional synapse organization in olfactory circuits and leverage behavior, circuit interaction studies, and functional imaging to determine how each specific aspect of of synapse structure regulates coordinated output of the circuit.
mechanisms of CNS synapse development
We combine the genetic advantages of Drosophila with in vivo biochemistry to delve deeper into the molecular mechanisms of synapses. We have identified a number of genes that regulate synapse formation in the CNS and are working towards understanding how they function. We discovered that the Teneurins, an emerging class of synapse organization molecules, control synapse number by regulating the presynaptic cytoskeleton (Mosca and Luo, eLife, 2014). Our past work identified LRP4 (Mosca et al., eLife, 2017) as a key presynaptic organizer of excitatory synapses (left). LRP4 functions through the activity of the SR-protein kinase SRPK79D to regulate synapse number and olfactory behavior. Current work (funded by the NIH through 2031) explores the mechanisms by which these genes function. Other projects in the lab study mutations that regulate synapse development, spacing, and size of active zones.
Sexually dimorphic synaptic development
One of the oldest questions in history has sought to understand the differences between the biological sexes. Sex differences in the brain in size, circuitry, behavior, metabolism, and cognition are well documented but their underlying molecular logic is largely unknown. This is exceedingly relevant translationally as a host of disorders show sexually dimorphic diagnosis rates and we lack a clear understanding why. Projects in the lab (starting from Aimino et al. Journal of Neuroscience, 2023) show that males and females have distinct synaptic developmental trajectories and are interested in understanding the molecular codes underlying such differences. Our recent work identified a sexually dimorphic code of transmembrane proteins that differentially regulate male and female synaptic development in neurons and glia. Currently, we are determining the molecular cascades that differentiate male and female synaptic development strategies and how they’re conserved.
Synaptic development and Maturation
Synaptic connections do not function perfectly on formation but mature over time to become robust, reliable connections. They recruit additional proteins and undergo functional changes to optimize output. Maturation failures underlie neuropsychiatric, neurodevelopmental, and neurodegenerative disorders. Our work identified novel roles for postsynaptic γ-secretase (Restrepo et al, Developmental Cell, 2022) and presynaptic LRP4 (DePew et al, Development, 2024) in promoting NMJ synapse maturation. But critical questions remain! Current work (funded by the NIH through 2028) will 1) identify new molecules that regulate synaptic maturation, 2) understand downstream mechanisms in maturation, and 3) determining how neurodegenerative risk genes influence maturation; all with the goal of connecting why failed maturation leads to neurological disorders in humans.