Paschalis Kratsios

Assistant Professor

Department of Neurobiology

The University of Chicago
947 E. 58th St., MC0928, 
Chicago, IL 60637

Email: pkratsios@uchicago.edu
Phone: +1-773-702-7442
Office: Abbott building, Room AB412

Kratsios lab website

 

Research Summary

Locomotion is an ancient behavior displayed by vertebrate and invertebrate animals. Despite anatomical differences in the execution of locomotion 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 principles governing motor neuron diversity and motor circuit assembly.

 

Research Statement

Our laboratory focuses on three key questions:

  1. How is motor neuron diversity generated during development and maintained throughout life?
  2. What are the molecular mechanisms that ensure synapse formation and specificity within the motor circuit?
  3. Are there any evolutionarily conserved principles behind motor circuit assembly?

To address these questions, 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 the C.elegans motor circuit

Its simple nervous system (302 neurons that fall into 118 distinct neuron types), the ease to perform forward genetic screens, the fact that we know of every synapse for every single neuron (only organism to date with complete connectome), and the plethora of molecular markers that allow us to visualize specific neuron types with single-cell resolution make C.elegans an excellent model to study neuronal development. Specifically, our laboratory focuses on the C.elegans ventral nerve cord, which is populated with several distinct subtypes of motor neurons required for locomotion. By performing forward genetic screens, we have identified novel, evolutionarily conserved transcription factors required for motor neuron diversity and function. Using novel methodology, such as whole genome sequencing, CRISPR genome editing and cell type-specific transcriptome profiling, we aim to elucidate the gene regulatory mechanisms (transcription factors and their targets) that establish and maintain a functional motor circuit. By uncovering such mechanisms, we may be one step closer to understanding how distinct motor neuron subtypes develop as functional units and form specific synapses.

Can we translate our findings from C.elegans to more complex nervous systems?

We have shown 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. In an attempt 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 single UNC-3 ortholog in C. intestinalis (termed CiCOE) is also required for motor neuron terminal differentiation. This striking phylogenetic conservation throughout millions of years of evolution (from worms to simple chordates) reveals that we have discovered an ancient gene regulatory principle. Quite remarkably, UNC-3 orthologs are also expressed in spinal motor neurons in mice. Motivated by these observations, our laboratory aims to systematically test whether the function of the transcription factors we discover in C.elegans is conserved across phylogeny using mouse genetics and novel genomic approaches.

Outlook: A detailed understanding of how the motor circuit develops and functions 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 transcription factors, their targets and the cis-regulatory elements (motifs) through which these factors act. Such decoding of cis-regulatory information is a vital step to fully comprehend genome function.

Selected publications

Kerk SY, Kratsios P*, Hart M, Mourao R, Hobert O*. Diversification of C. elegans Motor Neuron Identity via Selective Effector Gene Repression. Neuron. 2017 Jan 4;93(1):80-98. doi:10.1016/j.neuron.2016.11.036. *co-corresponding author

Pereira L, Kratsios P*, Serrano-Saiz E*, Sheftel H, Mayo AE, Hall DH, White JG, LeBoeuf B, Garcia LR, Alon U, Hobert O. A cellular and regulatory map of the cholinergic nervous system of C. elegans. Elife 2015 Dec 25;4. pii: e12432. doi: 10.7554/eLife.12432. *equal contribution

Kratsios P, Pinan-Lucarré B, Kerk SY, Weinreb A, Bessereau JL, Hobert O. (2015) Transcriptional coordination of synaptogenesis and neurotransmitter signaling. Current Biology 25(10):1282-95. This article was highlighted in the F1000.

Kratsios P, Alberto S, Levine M, Hobert O. (2012) Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene. Nature Neuroscience 15(2):205-14. Selected for the cover of Nature Neuroscience and highlighted in the F1000.                                                                                         

Tursun B, Patel T, Kratsios P, Hobert O. (2011) Direct Conversion of C.elegans Germ Cells into Specific Neuron Types. Science 331(6015):304-8.                 This article was highlighted in Nat Methods (2011) 8(2):112, Science (2011) 331(6015):292-3, and Nat Rev Neurosci. (2011) 12(2):60.