Symposium on Molecular and Cellular Basis of Neural Circuit Development and Regeneration
时间：2013年9月23日，13:00 - 17:30
1. Ben Novitch, University of California, Los Angeles
“Molecular Mechanisms Regulating Neural Progenitor Maintenance and Differentiation”
Within the developing and adult nervous system, neural stem and progenitor cells are organized in an epithelial sheet that encourages contacts between the cells to maintain their capacity for self-renewal and promote the growth of neural tissues. In order for cells to differentiate, they must shed these adhesive contacts, but the mechanisms regulating this process are largely unknown. Recent work from our laboratory has identified the Foxp family of transcription factors as critical regulators of this process. During embryonic development, Foxp4 and Foxp2 expression levels rise as neurons begin to form, and this increase coincides with the loss of key stem cell maintenance factors such as the adhesion protein N-cadherin and the transcriptional regulator Sox2. When Foxp4 and Foxp2 activities are experimentally elevated, the adhesive epithelial contacts between neural progenitors are lost, causing premature neuronal differentiation and depletion of the progenitor pool. In contrast, when Foxp4 and Foxp2 activities are eliminated, cells become overly adherent and are unable to differentiate, resulting in a spectrum of structural defects in both the spinal cord and brain. Together, our studies data reveal a novel Foxp-based transcriptional mechanism that regulates the integrity and cytoarchitecture of neuroepithelial progenitors throughout the central nervous system. These findings may be further relevant for our understanding of the mechanisms behind neurodevelopmental defects, as mutations in Foxp proteins have previously been associated with a range of intellectual disabilities and speech-language disorders such as autism, as well as proliferative diseases such as cancer.
2. Samantha Butler, University of California, Los Angeles
“Regulating axon outgrowth in the developing and regenerating nervous system”
During development, axons extend along stereotyped pathways to form the precisely ordered neuronal networks critical for the nervous system to function. Axons are guided into and along these pathways by processing directional information present in the embryonic environment. These guidance signals orient axons by locally polymerizing or depolymerizing the actin cytoskeleton in the growth cone. Our studies have shown that there are also “temporal” guidance signals, such as the Bone Morphogenetic Proteins (BMPs), that regulate the speed of axon outgrowth by controlling the rate at which actin polymerizes, or “treadmills”, in the growth cone. Temporal guidance cues permit axons to encounter directional information at the right time in development so that the neural circuits develop in synchrony with the developing embryo. In recent studies, we have now shown that this mechanism can be co-opted to accelerate the growth rate of regenerating peripheral nerves. Even though axon regeneration can occur in the peripheral nervous system, growth is sufficiently slow (1–2 mm/day) that it can take more than a year for peripheral axons to grow back to their targets. The denervated target muscles often atrophy during this period resulting in inadequate functional recovery. Thus, a method that accelerates the regenerative process may be of great therapeutic benefit to patients.
3. Anton Maximov, the Scripps Research Institute
“Experience-dependent and independent mechanisms of synapse formation and structural plasticity in the mammalian forebrain”
In the central nervous system, both the patterning of developing circuits and structural remodeling of established connections are regulated by neuronal activity. Experimental evidence suggests that different neuronal types exhibit remarkably different propensities to structural adaptation to experience, but the underlying mechanisms remain poorly understood. During my talk, I will focus on molecular basis of activity-dependent transcription of synapse-related genes, and will discuss the role of synaptic glutamate release in regulating the connectivity of specific excitatory and inhibitory neuronal types in the mammalian forebrain. I will also discuss new chemical-genetic approaches that enable rapid control of gene expression in brains of live and behaving animals.
4. Michael Granato, University of Pennsylvania
“Seeing is believing: peripheral nerve regeneration in live zebrafish”
Unlike axons of the central nervous system, axons of the peripheral nervous system have retained the capacity to regrow even after complete nerve transection. Yet despite their unique ability to re-make functional connections, we know remarkably little about how peripheral axons re-connect with their appropriate synaptic targets. This is in part because the dynamic behavior of injured or diseased axons as they respond to insults, interact with neighboring glia cells, and begin to pioneer a path to the original targets, has not been examined in real time, in intact vertebrate animals. Similarly, the signals that surrounding glia cells provide during the early phase of regeneration, and how changes in the extracellular matrix direct re-growing axons are not well understood. The goal of my laboratory is to define the cellular and molecular mechanisms that enable and direct regenerating peripheral axons to their synaptic targets. For this, we have established a laser based nerve transection model in zebrafish, enabling us to visualize the cellular behaviors of transected axons and neighboring cell types simultaneously, in real time, in an intact vertebrate animal. I will discuss ongoing projects to understand the interaction between injured axons and neighboring cell types, and how modification of the extracellular matrix enable re-growing axons to make navigational choices.
5. Yimin Zou, University of California, San Diego
“Neural circuit repair after spinal cord injury”
Axons in the mammalian central nervous system do not regenerate after injury. This is due to the lack of intrinsic growth capacity and the presence of strong inhibition in the environment. Although significant efforts have been dedicated to treat spinal cord injury, functional recovery by restoring the original axonal connections has not been achieved in mammals. Increasing evidence suggests that functional recovery after spinal cord injury can be achieved by circuit relay or bypass promoted by a combination of electrical and pharmacological stimulation and rehabilitation. We show here, for the first time, that the molecular pathways that regulate axon plasticity can also be used to enhance the plasticity of proprioceptive sensory circuitry when combined with peripheral preconditioning and rehabilitation. Wnt signaling directs the growth of ascending and descending axons along the rostro-caudal axis of the developing spinal cord and limits adult axon regeneration after injury. We developed a novel, and more potent, form of peripheral preconditioning that utilizes chemically-induced demyelination without peripheral axotomy. When combined with this demyelination-mediated preconditioning and continuous weekly training, inhibition of Wnt signaling lead to robust recovery of hindlimb proprioceptive function after injury without regeneration of the original connections. These combinatorial approaches promoted axon regeneration and enhanced synaptic remapping on thalamic-projecting neurons below the lesion site, suggesting that enhanced circuit remodeling can achieve the functional recovery.