About

Lihsia Chen, PhD, is an Associate Professor and graduate faculty member specializing in Molecular Pharmacology and Therapeutics at the University of Minnesota. Her research focuses on the L1CAM family of cell adhesion molecules, which are crucial for nervous system development and function. Mutations in L1CAM are linked to neurological disorders such as the L1 neurological disorder, autism, schizophrenia, and addiction. Dr. Chen's laboratory uses C. elegans as a genetic model organism to dissect the roles and mechanisms of L1CAM proteins, particularly the two C. elegans L1CAM genes, lad-1/sax-7 and lad-2, which have distinct functions in maintaining neural organization and axon guidance. Her work has identified the importance of SAX-7's anchorage to the dystrophin- and spectrin-actin cytoskeletons, providing insights into neuropsychiatric and muscular dystrophy-related conditions. Additionally, her research explores SAX-7's role in synaptic function and investigates guidance cues and intracellular signaling pathways involved in axon migration mediated by LAD-2.

Research topics

• Biology
• Genetics
• Cell biology
• Neuroscience
• Internal medicine
• Pediatrics
• Intensive care medicine
• Bioinformatics
• Medicine
• Pathology

Selected publications

• Fluorescence Lifetime-Based FRET Biosensors for Monitoring N Terminal Domain-Dependent Interactions of TDP-43 in Living Cells: A Novel Approach for ALS and FTD Drug Discovery

  ACS Chemical Neuroscience · 2025-06-10 · 5 citations

  articleOpen access

  model. These findings establish both the biosensors and the HTS platform as innovative tools for TDP-43 drug discovery and support an exciting translational approach for targeting TDP-43 proteinopathies.

  PublisherDOI

• Fluorescence lifetime-based FRET biosensors for monitoring N-terminal domain interactions of TDP-43 in living cells: A novel resource for ALS and FTD drug discovery

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-10-12 · 3 citations

  preprintOpen access

  Abstract TAR DNA-binding protein 43 (TDP-43) pathological aggregates are widely implicated in Alzheimer’s disease, frontotemporal dementia and amyotrophic lateral sclerosis. While therapeutic platforms targeting TDP-43 have predominantly targeted its aggregation, recent findings suggest that loss of functional TDP-43 dimers and multimers — essential for RNA processing — occur upstream of aggregation and is driven through disruption of N-terminal domain (NTD) interactions. Here, we demonstrate that these interactions are targetable via cellular fluorescence lifetime-based FRET biosensors which we used to screen the FDA-approved Selleck library. Our NTD-specific hit ketoconazole rescues sorbitol-induced TDP-43 mislocalization and aggregation, and ameliorates TDP-43 induced downregulation of SREBP2, a TDP-43 mRNA binding target with known implication in ALS. In addition, ketoconazole improves neurite outgrowth in a TDP-43 overexpressing neuron model and motor dysfunction in TDP-43 overexpressing C. elegans. Taken together, our platform represents a novel approach for targeting NTD-dependent TDP-43 interactions, and the identification of ketoconazole validates an exciting translational premise for TDP-43 drug discovery.

  PublisherOA PDFDOI

• The L1CAM SAX-7 is an antagonistic modulator of Erk Signaling

  bioRxiv (Cold Spring Harbor Laboratory) · 2024

  Senior authorCorresponding
  • Biology
  • Cell biology
  • Neuroscience

  occurs not only in cholinergic neurons for coordinated locomotion, but also extends outside the nervous system, revealing novel roles for SAX-7/L1CAM in non-neuronal processes, including vulval development. Our genetic findings in both the nervous system and developing vulva are consistent with SAX-7/L1CAM acting as an antagonistic modulator of ERK signaling.

  PublisherOA PDFDOI

• Genetic etiologies and diagnostic methods for congenital ventriculomegaly and hydrocephalus: A scoping review

  Birth Defects Research · 2023 · 4 citations

  • Medicine
  • Intensive care medicine
  • Pediatrics

  BACKGROUND: Congenital hydrocephalus (CH) is a life-threatening neurological condition that results from an imbalance in production, flow, or absorption of cerebrospinal fluid. Predicted outcomes from in utero diagnosis are frequently unclear. Moreover, conventional treatments consisting primarily of antenatal and postnatal surgeries are often unsuccessful, leading to high mortality rates. Causes of CH can range from secondary insults to germline pathogenic variants, complicating diagnostic processes and treatment outcomes. Currently, an updated summary of CH genetic etiologies in conjunction with clinical testing methodologies is lacking. This review addresses this need by generating a centralized survey of known genetic causes and available molecular tests for CH. METHODS: The scoping review protocol was registered with the Open Science Framework and followed the Arksey and O'Malley framework and the Joanna Briggs Institute methodology. The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) was utilized to define search guidelines and screening criteria. RESULTS: Our survey revealed a high number of genetic etiologies associated with CH, ranging from single gene variants to multifactorial birth defects, and additionally uncovered diagnostic challenges that are further complicated by changes in testing approaches over the years. Furthermore, we discovered that most of the existing literature consists of case reports, underscoring the need for studies that utilize CH patient research cohorts as well as more mechanistic studies. CONCLUSIONS: The pursuit of such studies will facilitate novel gene discovery while recognizing phenotypic complexity. Addressing these research gaps could ultimately inform evidence-based diagnostic guidelines to improve patient care.

  PublisherOA PDFDOI

• A role for the Erk MAPK pathway in modulating SAX-7/L1CAM-dependent locomotion in <i>Caenorhabditis elegans</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2021-03-09

  preprintOpen accessSenior authorCorresponding

  Abstract L1CAMs are immunoglobulin cell adhesion molecules that play important roles in the development and function of the nervous system. In addition to being associated with autism and schizophrenia spectrum disorders, impaired L1CAM function also underlies the X-linked L1 syndrome, which encompasses a group of neurological conditions, including spastic paraplegia and congenital hydrocephalus. Previous studies on both vertebrate and invertebrate L1CAMs established conserved roles that include axon guidance, dendrite morphogenesis, synapse development, and maintenance of neural architecture. We previously identified a genetic interaction between the C. elegans L1CAM encoded by the sax-7 gene and RAB-3, a GTPase that functions in synaptic neurotransmission; rab-3; sax-7 animals exhibit synthetic locomotion abnormalities and neuronal dysfunction. In this study, we examine the significance of this genetic interaction and show that this synergism also occurs when loss of SAX-7 is combined with mutants of other genes encoding key players of the synaptic vesicle cycle. In contrast, sax-7 does not interact with genes that function in synaptogenesis. These findings suggest a post-developmental role for sax-7 in the regulation of synaptic activity. To further assess this possibility, we conducted electrophysiological recordings and ultrastructural analyses at neuromuscular junctions. Lastly, we performed a forward genetic screen for suppressors of the rab-3; sax-7 synthetic phenotypes, uncovering a role for the Mitogen-activated Protein Kinase (MAPK) pathway in promoting coordinated locomotion.

  PublisherOA PDFDOI

• A role for the Erk MAPK pathway in modulating SAX-7/L1CAM-dependent locomotion in <i>Caenorhabditis elegans</i>

  Genetics · 2021 · 8 citations

  Senior authorCorresponding
  • Biology
  • Genetics
  • Cell biology

  L1CAMs are immunoglobulin cell adhesion molecules that function in nervous system development and function. Besides being associated with autism and schizophrenia spectrum disorders, impaired L1CAM function also underlies the X-linked L1 syndrome, which encompasses a group of neurological conditions, including spastic paraplegia and congenital hydrocephalus. Studies on vertebrate and invertebrate L1CAMs established conserved roles that include axon guidance, dendrite morphogenesis, synapse development, and maintenance of neural architecture. We previously identified a genetic interaction between the Caenorhabditis elegans L1CAM encoded by the sax-7 gene and RAB-3, a GTPase that functions in synaptic neurotransmission; rab-3; sax-7 mutant animals exhibit synthetic locomotion abnormalities and neuronal dysfunction. Here, we show that this synergism also occurs when loss of SAX-7 is combined with mutants of other genes encoding key players of the synaptic vesicle (SV) cycle. In contrast, sax-7 does not interact with genes that function in synaptogenesis. These findings suggest a postdevelopmental role for sax-7 in the regulation of synaptic activity. To assess this possibility, we conducted electrophysiological recordings and ultrastructural analyses at neuromuscular junctions; these analyses did not reveal obvious synaptic abnormalities. Lastly, based on a forward genetic screen for suppressors of the rab-3; sax-7 synthetic phenotypes, we determined that mutants in the ERK Mitogen-activated Protein Kinase (MAPK) pathway can suppress the rab-3; sax-7 locomotion defects. Moreover, we established that Erk signaling acts in a subset of cholinergic neurons in the head to promote coordinated locomotion. In combination, these results suggest a modulatory role for Erk MAPK in L1CAM-dependent locomotion in C. elegans.

  PublisherOA PDFDOI

• Using C. elegans as a Model to Understand How sax-7 Effects Canal-Associated Neurons

  University of Minnesota Digital Conservancy (University of Minnesota) · 2021-01-01

  articleOpen access

  sax-7(0) Ras(gf) animals exhibit an abnormal positioning of CAN axon cell bodyOur results reveal that are morphological abnormalities in the CANs of sax-7(0) Ras(gf) animals.These defects may underlie the fluid buildup observed in sax-7(0) Ras(gf) animals.To test this possibility, we will examine for similar CAN defects in each single mutant, which do not exhibit fluid buildup.If each single mutant does not display the CAN defects, it suggests that the the combination of both mutations leads to observed CAN defects, which contributes to the fluid buildup in sax-7(0) Ras(gf) animals.On the other hand, if at least one single mutants also shows similar CAN defects, then the fluid buildup observed in sax-7(0) Ras(gf) animals may be caused by another as-yet-unidentified defect.In this study we only looked at WT and sax-7(0) Ras(gf) animals (crossed with the kyIs4 transgene).As stated in the discussion we would additionally like to explore how sax-7(0) and Ras(gf) single mutants affect the CANs.It is possible that single mutants do not display the same positional defects as double mutants and through this analysis we can assess the strength and extent of the synergistic effect between sax-7 and Ras.To begin, the following strains would be needed: Ras(gf) animals (crossed with the kyIs4 transgene) sax-7( 0) animals (crossed with the kyIs4 transgene) L1CAMs are transmembrane glycoproteins of the immunoglobulin (Ig) superfamily conserved from C. elegans to humans

  Publisher

• EFN-4/Ephrin functions in LAD-2/L1CAM-mediated axon guidance in <i>Caenorhabditis elegans</i>

  Development · 2016-01-01 · 11 citations

  articleOpen accessSenior author

  During development of the nervous system, growing axons rely on guidance molecules to direct axon pathfinding. A well-characterized family of guidance molecules are the membrane-associated ephrins, which together with their cognate Eph receptors, direct axon navigation in a contact-mediated fashion. InC. elegans, the ephrin-Eph signaling system is conserved and is best characterized for their roles in neuroblast migration during early embryogenesis. This study demonstrates a role for the C. elegans ephrin EFN-4 in axon guidance. We provide both genetic and biochemical evidence that is consistent with the C. elegans divergent L1 cell adhesion molecule LAD-2 acting as a non-canonical ephrin receptor to EFN-4 to promote axon guidance. We also show that EFN-4 probably functions as a diffusible factor because EFN-4 engineered to be soluble can promote LAD-2-mediated axon guidance. This study thus reveals a potential additional mechanism for ephrins in regulating axon guidance and expands the repertoire of receptors by which ephrins can signal.

  PublisherOA PDFDOI

• C. elegans NIMA-related kinases NEKL-2 and NEKL-3 are required for the completion of molting

  Developmental Biology · 2014-12-15 · 44 citations

  article
  PublisherDOI

• A Novel Nondevelopmental Role of the SAX-7/L1CAM Cell Adhesion Molecule in Synaptic Regulation in<i>Caenorhabditis elegans</i>

  Genetics · 2014-12-08 · 16 citations

  articleOpen accessSenior authorCorresponding

  The L1CAM family of cell adhesion molecules is a conserved set of single-pass transmembrane proteins that play diverse roles required for proper nervous system development and function. Mutations in L1CAMs can cause the neurological L1 syndrome and are associated with autism and neuropsychiatric disorders. L1CAM expression in the mature nervous system suggests additional functions besides the well-characterized developmental roles. In this study, we demonstrate that the gene encoding the Caenorhabditis elegans L1CAM, sax-7, genetically interacts with gtl-2, as well as with unc-13 and rab-3, genes that function in neurotransmission. These sax-7 genetic interactions result in synthetic phenotypes that are consistent with abnormal synaptic function. Using an inducible sax-7 expression system and pharmacological reagents that interfere with cholinergic transmission, we uncovered a previously uncharacterized nondevelopmental role for sax-7 that impinges on synaptic function.

  PublisherOA PDFDOI

Recent grants

• L1CAM adhesion and signaling pathways in C. elegans

  NIH · $3.9M · 2005–2024

Frequent coauthors

• Vann Bennett

  Duke Medical Center

  27 shared

• Andrew Fire

  Stanford University

  20 shared

• Michael Krause

  National Institutes of Health

  16 shared

• Si-Qun Xu

  National Institute of Diabetes and Digestive and Kidney Diseases

  9 shared

• Bryan Kit Teck Ong

  National University of Singapore

  9 shared

• Susan White Harrison

  Carnegie Institution for Science

  9 shared

• Suraj Moorthy

  Howard Hughes Medical Institute

  9 shared

• Melinda Moseley-Alldredge

  6 shared

Awards & honors

• Dr. James E. Rubin Medical Memorial Award
• Graduating Medical Student Research Award
• Veneziale-Steer Award
• Dr. Marvin and Hadassah Bacaner Research Awards
• Schmidt Steer Award