Research Summary

Locomotion is an ancient behavior displayed by vertebrate and invertebrate animals. Despite anatomical differences between species, locomotion invariably relies on the function of a specialized network of neuronal and muscle cells known as the motor circuit. Motor neurons lie at the heart of this circuit and display remarkable diversity based on anatomy, electrophysiology and molecular composition. Decades of research on motor neuron development and function have set the foundation upon which we intend to build and expand our knowledge on the molecular mechanisms underlying motor neuron diversity and motor circuit assembly. By focusing on motor neurons, we hope to reveal broadly applicable molecular mechanisms necessary for neuronal diversification and circuit assembly.

The research objectives of our lab are:
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1. To understand how motor neuron diversity is generated during development and maintained throughout life.
2. To uncover the molecular mechanisms that enable motor neurons to become and remain functional.
3. To reveal conserved and divergent molecular mechanisms underlying motor neuron development.
4. To study the molecular mechanisms that cause motor neuron disease.

To this end, we harness the specific strengths of two model organisms. We use the nematode Caenorhabditis elegans (C. elegans) as a gene discovery tool and then aim to translate our findings to the vertebrate nervous system using the mouse Mus musculus as a model.

​​Studying motor neuron development and disease in C. elegans

Its simple nervous system (302 neurons that fall into 118 distinct neuron types), the ease to perform forward genetic screens, its complete connectome, and the plethora of available molecular markers for specific neuron types make C.elegans an excellent model to study neuronal development. Specifically, our lab focuses on the C. elegans ventral nerve cord, which is populated with distinct subtypes of cholinergic and GABAergic motor neurons necessary for locomotion. By performing forward genetic screens, we identified novel, evolutionarily conserved regulatory factors (e.g., transcription factors, chromatin factors) required for motor neuron diversity and function. Using state-of-the-art methodology including whole genome sequencing, CRISPR/Cas9 genome editing, single-molecule mRNA fluorescent in situ hybridization (FISH) and cell type-specific transcriptome profiling, we aim to elucidate the gene regulatory mechanisms that enable motor neurons to mature and become functional. 

More recently, our lab became interested in the molecular mechanisms underlying motor neuron disease. In collaboration with the Roos lab (Neurology, U Chicago), we developed a new C. elegans model that recapitulates aspects of motor neuron disease (ALS). Check our collaborative paper here: https://doi.org/10.1101/2020.06.13.150029

​Can we translate our C. elegans findings to the mouse spinal cord?

We previously showed that the phylogenetically conserved COE (Collier, Olf, EBF)-type transcription factor UNC-3 is required for terminal differentiation of the majority of C.elegans nerve cord motor neurons 
(PMID: 22119902, PMID: 25913400). To extend our findings to more complex nervous systems, we used the simple chordate Ciona intestinalis (in collaboration with the lab of Michael Levine) and found that the UNC-3 ortholog in C. intestinalis (CiCOE) is also required for motor neuron terminal differentiation 
(PMID: 22119902). This striking phylogenetic conservation throughout millions of years of evolution (from worms to simple chordates) suggests an ancient role for UNC-3. Intriguingly, UNC-3 orthologs are also expressed in the mouse spinal cord.

Motor neuron axonal projections to the mouse forelimb

Motor neurons in the mouse embryonic spinal cord

​Our recent study (PMID: 30658714) suggests that the function of UNC-3 is conserved in mouse spinal motor neurons. Motivated by these observations, our lab aims to systematically test whether the function of other transcription factors we study in C. elegans (e.g., Hox family of TFs) is conserved across phylogeny. To this end, we employ conditional mouse mutagenesis (Cre/loxP technology) combined with cutting-edge molecular (e.g., RNA-Seq) and behavioral approaches.

​Outlook

A detailed understanding of how motor neurons develop and function may provide novel entry points into the etiology, diagnosis or treatment of motor neuron disorders, such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). From the basic science perspective, our research will reveal novel regulatory factors (e.g., transcription factors, chromatin factors) and the molecular mechanisms through which these factors act to control motor neuron development.