Our current research focuses on how aging processes change the new axonal connections in adult hippocampus. We have been using an inducible genetic labeling technique that allows us to control the number of labeled newborn neurons at any age throughout adult life. This mouse line (GliCreER) carries the tamoxifen-inducible CreERprotein under the control of a Sonic hedgehog-responsive Gli1 promoter element, which is specifically activated in neural precursor cells. When crossed to reporter mouse lines, GliCreERmice express fluorescent markers only in progenitors and newborn neurons in the DG. The number of labeled neurons can be controlled by the amount of tamoxifen that is injected.
Our current working hypothesis is that the developmental origin, molecular identity, cellular differentiation, and synaptic integration of neuronal progenitors are significantly changed or compromised during the aging process. We plan to systematically determine the molecular and cellular changes critical for establishing synaptic integration during AHN in young and aged brain. Despite a rich knowledge of the roles of molecular, cellular, and neural activities in regulating AHN, the reasons why neurogenesis is less efficient in the aged hippocampus are still poorly defined. We hope to identify the mechanisms that regulate the formation of newborn GCs in the aged hippocampus, thereby filling a major gap in our current understanding of neurogenesis in the aged brain.
(I) Our early research work laid the foundation for the use of AP (alkaline phosphatase) fusion protein techniques and the molecular mechanisms of topographic map in the visual system. Prior to our early research, Ephswere orphan receptors without known functions. We developed the AP fusion expression cloning techniques and identified ephrins. We then developed the RAP (receptor AP) and LAP (Ligand AP) to demonstrate Ephsand ephrinsare the “Sperry” molecules for establishing the visual topographic map. Both the AP fusion technique and the biology of Ephsand ephrinsin the formation of topographic neural circuits have contributed significantly to the progress of the field.
(II) Using mouse genetics, we generated plexin mutant mice to address the in vivo functions of semaphorin-plexin signaling in axon guidance. These studies demonstrated the differential roles of plexin family members in guiding axons in vivo, and unexpectedly revealed the role of semaphorin-plexin signaling in regulating stereotyped axon pruning in the central nervous system.
(III) To understand the signaling pathways that regulate axon repulsion, we turned to C. elegans genetics and isolated max (motor neuron axon guidance) mutants. We identified and cloned max-1 and max-2. We demonstrated that MAX-1 is involved in AP3-mediated trafficking and degradation of UNC-5 receptor through SUMOylation regulation. We also showed that MAX-2 is a major downstream effector of RAC GTPases that are required for the repulsion of motor axons. These studies provided a foundation for investigating the role of the schizophrenia-related gene disc1 in neural development. By combining C. elegans and mouse genetics, we revealed the previously unknown function of disc1 in regulation of adult-generated neurons in the hippocampus and established a heterologous transgenic disc1 line in C. elegans.
(IV) Axon pruning in the brain had been recognized as a fundamental process for developmental plasticity, but the understanding of the molecular and cellular regulations for this process had been challenging. Focusing on the pruning events in hippocampal and visual circuits, we developed immuno-electron microscopic and imaging analysis to investigate the cellular mechanisms. These studies demonstrated that the axon branches to be pruned often form synapses, suggesting the importance of neural activity for the process.
(V) Using ferret as a model, we studied the role of neural activity in refining the anatomical and functional connections of the visual system. We had identified activity-dependent axon-axon competition as an important mechanism for axon terminal targeting during development and revealed the role of stage III retinal waves in promoting circuit refinement.
The Scientist Magazine: Cutting Neurons Down To Size
Sience Volume 274, Number 5293, pp. 1637: Pharmacia Biotech & Science Prize
Grand Prize Winner
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