The goal of Dr. Lizhen Chen's research is to discover molecular pathways involved in neuronal aging and disease, and to translate such findings into potential therapeutic targets. Specifically, our research focuses on molecular mechanisms of neuronal aging, degeneration and age-dependent axon regeneration. We use C. elegans and mouse models in our research. The short life span and powerful genetics of C. elegans offers unique advantage for understanding the molecular and cellular mechanisms underlying neuronal aging. The findings from C. elegans will then be applied to mammals. We are currently working on the following projects:
Regulation of MT dynamics in neuronal responses to age and injury
Axons in the central nervous system of adult mammals fail to regenerate after injury. In contrary, embryonic and early postnatal animals show a remarkable ability to regenerate axons. Despite decades of studies, the age-dependent changes and the factors influencing this transition remain largely unknown. The importance of MT regulation in neuron aging is underscored by the dysfunction of MT stabilization proteins in age-dependent neurodegeneration and the effect of drugs targeting MT stability in altering the pathogenic symptoms in animal models of neurodegenerative diseases. Age-dependent deterioration in neuronal morphology and disorganized MT arrays has been reported, but the MT dynamics in aged neurons has received little attention. MT plus ends are constantly undergoing growth and shrinkage, while the minus ends are relatively less dynamics. We have previously used a MT plus end marker EBP-2::GFP to study MT growth in injured axons. We aim to understand age-associated changes in MT organization and dynamics, and their effect on neuronal aging and regeneration.
CELF-mediated alternative splicing in neurodegeneration
Alternative splicing is a fundamental mechanism in gene expression regulation. Alternative splicing have been previously implicated in the context of Alzheimer’s disease (AD). For example, alternative splicing of exon 10 of the tau primary transcript generates isoforms of tau protein with three or four microtubule binding repeats. Imbalances in the ratio of three to four-repeat tau are known to induce pathological changes in a human-Tau mouse model. CELF family of RNA binding proteins are expressed in the nervous system and involved in RNA splicing. Recent GWAS analyses have identified CELF proteins as risk factors of AD. We have conducted CLIP-seq on CELF proteins and found that CELF RBPs bind to mRNAs of AD-related genes and the binding sites are proximate to the alternatively spliced exons, suggesting that CELF RBPs might be involved in alternative splicing of these AD-related genes. We are currently testing the hypothesis that CELF RBPs co-regulate splicing of a set of AD-related genes and manipulating CELF expression can influence the ratio of splicing isoforms and subsequently impact neuronal health.
Chen L, Liu Z, Zhou B, Wei C, Zhou Y, Rosenfeld MG, Fu XD, Chisholm AD, Jin Y. CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins. Elife. 2016 Jun 2;5. pii: e16072. doi: 10.7554/eLife.16072. [Epub ahead of print] PubMed PMID: 27253061.
Chen L, Chuang M, Koorman T, Boxem M, Chisholm A and Jin Y (2015) Axon injury triggers EFA-6 mediated destabilization of axonal microtubules via TACC and doublecortin like kinase. eLife.08695. PMID: 26339988
Grill B, Chen L, Bienvenut W, Anderson M, Quadroni M, Jin Y and Garner CC (2012) RAE-1 a novel PHR binding protein is required for axon termination in C. elegans. Journal of Neuroscience 32(8):2628-36 PMID: 22357847
Chen L, Wang Z, Hubert T, Ghosh-Roy A, O’ Rourke S, Bowerman B, Wu Z, Jin Y, Chisholm A. (2011) Axon regeneration pathways identified by systematic genetic screening in C. elegans. Neuron 71(6):1043-57 PMID: 21943602
Chen L and Chisholm A. (2011) Axon regeneration mechanisms: insights from C.elegans. Trends in Cell Biology 21(10):577-84 PMID: 21907582
Chen L, Zhao P, Wells L, Amemiya C, Condie B, Manley N. (2010) Mouse and zebrafish Hoxa3 orthologs have non-equivalent in vivo protein function. PNAS vol. 107 no. 23 10555-10560 PMID: 20498049
Liu Z, Farley A, Chen L, Kirby BJ, Kovacs CS, Blackburn C, Manley N. (2010) Thymus-associated parathyroid hormone has two cellular origins with distinct endocrine and immunological functions. PLoS Genetics 6(12): e1001251 PMID: 21203493
Wang ZR, Guo L, Chen L, McEachern MJ. (2009) Evidence for an additional base-pairing element between the telomeric repeat and the telomerase RNA template in Kluyveromyces lactis and other yeasts. Mol Cell Bio.29(20):5389-98 PMID: 19687297
Chen L, Xiao S, Manley N. (2009) Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood. 113(3):567-74 PMID: 18978204