Le Ma, PhD
Philadelphia, PA 19107
Research and Clinical Interests
How to Build and Rebuild Neural Networks From Axons and Dendrites?
One remarkable feature of the nervous system is the web-like networks linking axons and dendrites, the long and thin extensions form nerve cell bodies. These intricate networks are responsible for sophisticated behaviors, such as walking and talking. They are built by a series of developmental processes, including the formation of nerve branches that allow dendrites to maximize synaptic inputs and axons to relay outputs to multiple targets. Although elaborate nerve branches are known for more than a century and often associated with specific cell types and functions, the mechanisms underlying their development and regulation are not well understood. How do they form at the right time and in the right place? How do they attain specific pattern and size? How do they remodel in response to experience or injury? And, how do they contribute to brain disorders and nerve regeneration? To address these fundamental questions, three major research directions are currently being pursued in the laboratory.
1) Identify molecular pathways involved in branching. Using mammalian neuronal cell models, we investigate known factors in controlling stereotypic branched patterns and search new genes that are critical to regulating different aspects of branching. A variety of modern molecular techniques, such as RNAseq and CRISPR, are combined with primary cell culture and in vivo analysis in these studies. For examples, a) following sensory neurons in the dorsal root ganglion, we have identified two signaling mechanisms required for proper bifurcation during early spinal cord development; and b) using a viral delivery technique to inactivate gene function while simultaneously visualizing single cell morphology, we have identified a cell surface signaling system required for dendrite self-avoidance, a patterning mechanism generating elaborated branches that rarely overlap, in cerebellar Purkinje cells.
2) Explore cell biological regulation of branching. Although branched morphologies come in different shape and size, only a limited number of factors are encoded by the genome. To understand how branching patterns are defined by a combination of environmental cues and intrinsic programs, we investigate the cooperation of molecules that regulates different steps of branching, including initiation, growth, guidance, stabilization, and patterning. Cutting-edge cell biological tools, including live cell imaging, micro-patterning, and computer vision, are employed here to examine the regulation of cellular machineries during branch development.
3) Define the contribution of branching to circuit function and repair. Branching morphogenesis is essential to generating complex neural networks, but what is the physiological consequence when branching regulation is perturbed? How are they affected in neurological and psychiatric disorders? Knowledge of molecular pathways coupled to the anatomically robust phenotypes offers us a unique opportunity to: a) investigate the contribution of nerve branching to normal circuit functions using a battery of behavioral assays, and b) identify potential animal models that mirror commonly seen disease phenotypes. In addition, we are interested in the response of nerve branches to degeneration associated with many diseases as well as the potential to translate our newly acquired knowledge from developmental studies of branching to nerve regeneration in adults.
Most Recent Peer-Reviewed Publications
- MAP7 regulates axon collateral branch development in dorsal root ganglion neurons
- Dcc Mediates Functional Assembly of Peripheral Auditory Circuits
- Dendrite self-avoidance requires cell-autonomous slit/robo signaling in cerebellar purkinje cells
- Mutation of Npr2 Leads to Blurred Tonotopic Organization of Central Auditory Circuits in Mice
- CNP/cGMP signaling regulates axon branching and growth by modulating microtubule polymerization
- Axon Growth and Branching
- Slit/Robo signaling mediates spatial positioning of spiral ganglion neurons during development of cochlear innervation
- Roundabout Receptors Are Critical for Foregut Separation from the Body Wall
- Dystroglycan Organizes Axon Guidance Cue Localization and Axonal Pathfinding
- Visualization and Analysis of Microtubule Dynamics Using Dual Color-Coded Display of Plus-End Labels
- Slit/Robo Signaling Modulates the Proliferation of Central Nervous System Progenitors
- Slits affect the timely migration of neural crest cells via robo receptor
- Mosaic analysis of gene function in postnatal mouse brain development by using virus-based cre recombination
- Developmental regulation of axon branching in the vertebrate nervous system
- Presenilin-dependent receptor processing is required for axon guidance
- Axon Guidance: Guidance Cues and Guidepost Cells
- The development of peripheral cold neural circuits based on TRPM8 expression
- Regulation of axonal development by natriuretic peptide hormones
- Transient cell-cell interactions in neural circuit formation
- Regulate axon branching by the cyclic GMP pathway via inhibition of glycogen synthase kinase 3 in dorsal root ganglion sensory neurons