•Rem2 signaling regulates gene expression.•Rem2 signaling promotes the expression of known synaptogenic factors Lrrtm4 and Gpc5.•The Gpc5 ligand functions in the postsynaptic neuron to regulate excitatory synapse formation.•Rem2 both promotes and represses gene expression in the context of neuronal depolarization.•Rem2 knockdown modulates activity-dependent transcriptional pathways.The central nervous system has the remarkable ability to convert changes in the environment in the form of sensory experience into long-term alterations in synaptic connections and dendritic arborization, in part through changes in gene expression. Surprisingly, the molecular mechanisms that translate neuronal activity into changes in neuronal connectivity and morphology remain elusive. Rem2, a member of the Rad/Rem/Rem2/Gem/Kir (RGK) subfamily of small Ras-like GTPases, is a positive regulator of synapse formation and negative regulator of dendritic arborization. Here we identify that one output of Rem2 signaling is the regulation of gene expression. Specifically, we demonstrate that Rem2 signaling modulates the expression of genes required for a variety of cellular processes from neurite extension to synapse formation and synaptic function. Our results highlight Rem2 as a unique molecule that transduces changes in neuronal activity detected at the cell membrane to morphologically relevant changes in gene expression in the nucleus.

Metalloproteases regulate a vast array of critical cellular processes such as proliferation, migration, repair, and invasion/metastasis. In so doing, metalloproteases have been shown to play key roles in the pathogenesis of multiple disorders including arteriosclerosis, arthritis, cancer metastasis, and ischemic brain injury. Therefore, much work has focused on developing metalloprotease inhibitors to provide a potential therapeutic benefit against the progression of these and other diseases. In order to produce a more potent inhibitor of metalloproteases, we synthesized multivalent displays of a metalloprotease inhibitor derived from the ring-opening metathesis polymerization (ROMP). Specifically, multivalent ligands of a broad-spectrum metalloprotease inhibitor, TAPI-2, were generated upon conjugation of the amine-bearing inhibitor with the ROMP-derived N-hydroxysuccinimide ester polymer. By monitoring the metalloprotease dependent cleavage of the transmembrane protein Semaphorin4D (Sema4D), we demonstrated an enhancement of inhibition by multivalent TAPI-2 compared to monovalent TAPI-2. To further optimize the potency of the multivalent inhibitor, we systematically varied the polymer length and inhibitor ligand density (mole fraction, χ). We observed that while ligand density plays a modest role in the potency of inhibition caused by the multivalent TAPI-2 display, the length of the polymer produces a much greater effect on inhibitor potency, with the shortest polymer achieving the greatest level of inhibition. These findings validate the use of multivalent display to enhance the potency of metalloprotease inhibitors and further, suggest this may be a useful approach to enhance potency of other small molecule towards their targets.

•Dendritic morphology is dynamic and regulated in part by neuronal activity.•Positive and negative molecular regulators contribute to activity-mediated morphology.•The identification of molecular regulators of morphology is a major research area.•RGK proteins have recently emerged as activity-dependent regulators of morphology.The nervous system has the amazing capacity to transform sensory experience from the environment into changes in neuronal activity that, in turn, cause long-lasting alterations in neuronal morphology. Recent findings indicate that, surprisingly, sensory experience concurrently activates molecular signaling pathways that both promote and inhibit dendritic complexity. Historically, a number of positive regulators of activity-dependent dendritic complexity have been described, whereas the list of identified negative regulators of this process is much shorter. In recent years, there has been an emerging appreciation of the importance of the Rad/Rem/Rem2/Gem/Kir (RGK) GTPases as mediators of activity-dependent structural plasticity. In the following review, we discuss the traditional view of RGK proteins, as well as our evolving understanding of the role of these proteins in instructing structural plasticity.

Glutamatergic synapse development has been rigorously investigated for the past two decades at both the molecular and cell biological level yet a comparable intensity of investigation into the cellular and molecular mechanisms of GABAergic synapse development has been lacking until relatively recently. This review will provide a detailed overview of the current understanding of GABAergic synapse development with a particular emphasis on assembly of synaptic components, molecular mechanisms of synaptic development, and a subset of human disorders which manifest when GABAergic synapse development is disrupted. An unexpected and emerging theme from these studies is that glutamatergic and GABAergic synapse development share a number of overlapping molecular and cell biological mechanisms that will be emphasized in this review.Highlights► Glutamatergic and GABAergic synapses differ at the ultrastructural and molecular level. ► Thus far, little is known about the order of assembly of components at GABAergic synapses. ► Many molecules mediate both glutamatergic and GABAergic synapse development. ► The depolarizing action of GABA-mediated currents drives glutamatergic synapse development. ► An underlying cause of neurological disease is aberrant GABAergic synapse development.