Signaling Networks Regulating Neuronal Connectivity in Brain Development and Disease

The chief goals of our research are to identify the fundamental principles and mechanisms that govern the assembly and function of neural circuits in the developing brain and to determine how these mechanisms are deregulated in neurological disorders. The morphogenesis of axons and dendrites and formation and refinement of synapses represent key steps in the establishment of neural circuits in the brain. Our laboratory has discovered some of the first fundamental transcriptional, epigenetic, and ubiquitin-signaling networks that govern neuronal morphogenesis and synaptic connectivity in the mammalian brain, thus establishing the field of cell-intrinsic regulation of neuronal connectivity. In recent studies, we have elucidated how deregulation of cell-intrinsic mechanisms of neuronal morphogenesis and connectivity contributes to neurodevelopmental disorders of cognition. Our research is organized in three major areas.

Epigenetic and transcriptional control of synaptic connectivity

In one set of studies, we have discovered a function for the transcription factor MEF2A in synaptic connectivity in the cerebellum. Remarkably, a sumoylated transcriptional repressor form of MEF2A drives the formation of both the postsynaptic dendritic claws and presynaptic boutons of granule neurons in the cerebellar cortex. In other studies, we have discovered functions for the major transcriptional regulators SnoN1, FOXO1, FOXO6, NeuroD, NeuroD2, Id1, and Id2 as components of critical regulatory networks that control key aspects of neuronal morphogenesis connectivity in the cerebellum (Figure 1).

Our studies have established the principle that different transcriptional regulators are dedicated to distinct phases of neuronal morphogenesis and connectivity from polarization and axon growth to migration and positioning to dendrite and synapse differentiation. In recent studies, we have discovered that the NuRD chromatin remodeling complex decommissions the promoters of developmentally regulated genes and thereby drives an epigenetic program of synaptic connectivity in the mammalian brain

Regulation of neuronal connectivity by ubiquitin signaling

Our studies suggest that ubiquitin ligases play also prominent roles in neuronal connectivity. We have discovered functions for the ubiquitin ligases Cdh1-anaphase promoting complex (Cdh1-APC), Cdc20-APC, and Cul7Fbxw8 in the regulation of axon and dendrite morphogenesis as well as synapse differentiation in the cerebellar cortex (Figure 2).

Our studies have established the principle that spatial localization of ubiquitin ligases plays a critical role in neuronal morphogenesis and connectivity in the brain. The ubiquitin ligase Cdc20-APC localizes to the centrosome and thereby drives the elaboration of granule neuron dendrite arbors in the cerebellar cortex. By contrast, the nucleus and the Golgi apparatus represent the sites of action for Cdh1-APC and Cul7Fbxw8 in the control of granule neuron axon and dendrite morphogenesis, respectively. In current studies, we are probing the role of autism-linked ubiquitin ligases in synapse differentiation and function in the mammalian brain.

Deregulation of neuronal connectivity in intellectual disability and autism

Our understanding of the pathogenic mechanisms underlying autism and related cognitive disorders remains rudimentary. With our perspective of cell-intrinsic regulation of neuronal connectivity, we are poised to provide novel insights into the pathogenesis of neurodevelopmental disorders of cognition. In one set of studies, beginning with a targeted screen of X-linked intellectual disability genes, we have unexpectedly found that the nuclear protein PQBP1 also localizes at the base of the primary cilium in post-mitotic neurons where PQBP1 regulates the GTPase Dynamin 2 and thereby drives ciliogenesis in the mammalian brain. Patient-specific mutations of PQBP1 disrupt its ability to regulate Dynamin 2 and drive ciliogenesis, suggesting that the novel function of PQBP1 is pathophysiologically relevant. In other studies, we have discovered that the X-linked intellectual disability protein PHF6 and the PAF1 transcription elongation complex form components of a novel pathophysiologically relevant pathway that regulates neuronal migration in the brain. Remarkably, impairment of PHF6 function leads to white matter heterotopias and neuronal hyperexcitability. In addition to extending studies of PHF6, we are currently probing how deregulation of epigenetic control of neuronal connectivity contributes to the pathogenesis of autism spectrum disorders.