The focus of our research is to address:
- how neuronal development contributes to the assembly and function of the nervous system
- how defects in this process lead to brain disorders
On neuronal development, we are interested in how neurons develop dendrites and axons into distinct subcellular compartments and how experience interacts with the genome to shape the nervous system. On brain disorders, we investigate the role of dysregulated expression levels of genes (e.g., in Down syndrome). We use both Drosophila and mouse models in our research and take a multi-disciplinary approach that include genetics, cell biology, developmental biology, biochemistry, advanced imaging (for neuronal structures and activity), electrophysiology, computation and behavioral studies.
The differential growth of dendrites and axons
Dendrites and axons are the input and output compartments of a neuron, respectively.
Knowledge of the mechanisms underlying the separation of dendritic and axonal compartments is not only crucial for understanding the assembly of neural circuits, but also for developing strategies to correct defective dendrites or axons in diseases with subcellular precision. We previously conducted a forward genetic screen in Drosophila and identified several genes that specifically control dendritic and axonal growth (Ye et al., 2007; Grueber et al., 2007).
By studying the genes identified through this screen, we discovered that dendritic and axonal growth exhibit distinct dependence on the function of the secretory pathway (Ye 2007), and that dendritic and axonal growth can be separated at the transcriptional level by the gene dendritic arbor reduction 1 (dar1) (Ye et al., 2011).
Recently, we discovered a bimodal mechanism that that controls dendritic and axonal growth in opposite directions in vivo (Wang et al., 2013). Specifically, the Dual Lucine Zipper Kinase (DLK), which is known to promote axon regeneration after nerve injury, has the opposite effect on the dendrites: enhanced DLK activity leads to diminished dendrites. This finding calls attention to the need to look at the other side (i.e. the dendrites) of a neuron when developing new therapies for axon regeneration. The signaling mechanism identified by this study also provides insight into how we may tune the DLK signaling to specifically control axonal growth.
We are currently testing whether the bimodal regulation of dendritic and axonal growth by DLK is a common mechanism in Drosophila and mouse.
Axonal Arbor Development: Size Control Versus Patterning
Expression of the Down syndrome cell-adhesion molecule (Dscam) is increased in the brains of patients with several neurological disorders.
It is known that, in both Drosophila and mammals, Dscam is critical for self-avoidance between the neurites of the same neuron and for axonal targeting. However, little is known about either the mechanism that regulates its expression nor the functional consequences of dysregulated Dscam expression. We recently discovered that Dscam expression levels serve as an instructive code that controls the size of the presynaptic arbor (Kim, Wang, et al., 2013).
Our study shows that while isoform diversity of Dscam is critical for presynaptic arbor targeting, Dscam expression level determines the size of the presynaptic arbor. Two convergent pathways, involving Dual Leucine Zipper Kinase (DLK) and fragile X mental retardation protein (FMRP), control Dscam expression through protein translation.
Defects in this regulation of Dscam translation lead to exuberant presynaptic arbor growth in Drosophila sensory neurons. These findings demonstrate a previously unknown aspect of Dscam function and provide insights into how dysregulated Dscam may contribute to the pathogenesis of neurological disorders. We are currently testing the effects of overexpression of Dscam in mice to see how it changes both the development of the nervous system and the animal’s behavior.
Organelle polarity in neurons: Dendritic Golgi outposts
One notable difference between dendrites and axons is the differential distribution of dendritic Golgi outposts, membranous organelles that contain Golgi resident proteins (Ye et al., 2007). The Ye lab reported the first study demonstrating a fundamental difference between the Golgi found in dendrites and those residing in the cell body of neurons (Zhou et al., 2014). This study also debuted a toolbox for studying the Golgi complex in vivo in multi-cellular organisms.
Experience-dependent sensory perception
The Ye lab established a novel system for mechanistic analysis of the plasticity of developing neural circuits by showing that sensory experience during development alters nociceptive behavior and circuit physiology in Drosophila larvae.
Despite the convergence of nociceptive and gentle mechanosensory inputs on common second-order neurons (SONs), developmental noxious input modifies transmission from nociceptors to their SONs, but not from mechanosensors to the same SONs, which suggests striking sensory pathway specificity in this form of plasticity. These SONs activate serotonergic neurons to inhibit nociceptor-to-SON transmission; stimulation of nociceptors during development sensitizes nociceptor presynapses to this feedback inhibition.
This study demonstrates that, unlike associative learning, which involves the association of two sensory pathways through serotonergic modulation, sensory pathway-specific plasticity can be in part established through feedback serotonergic modulation within the same sensory pathway.
Mechanisms and therapeutics of neurodevelopmental diseases
During our investigation of axon-specific development, we discovered that the expression level of Dscam instructs the growth of axon terminals (Kim, Wang, et al., 2013). The regulation and function of Dscam levels are important, not only because they are essential for our understanding of neuronal development, but also because in several brain disorders Dscam levels are dysregulated in patient brains.
Our findings suggest a novel molecular link between Down syndrome and Fragile X syndrome, which are the most prevalent genetic causes of intellectual disability. Currently, there is no effective treatment for either disorder.
With the goal of developing therapeutics for patients with Down and Fragile X syndromes, we attempted to suppress hyperactive Dscam signaling and discovered that the cytoplasmic tyrosine kinase, Abl, is required for dysregulated Dscam levels to promote presynaptic terminal growth (Sterne et al., 2015). Furthermore, administration of FDA-approved Abl kinase inhibitors mitigates the developmental consequences of increased Dscam expression in Drosophila in vivo. These results suggest that administration of Abl inhibitors may attenuate the neurological defects of Down syndrome and Fragile X syndrome.