Jeremy Nance, PhD

Jeremy NanceAssociate Professor of Cell Biology
Ph.D., 1999 The University of Arizona

Developmental Genetics Program
Skirball Institute of Biomolecular Medicine
New York University School of Medicine
540 First Ave. 4th floor
New York, NY 10016
Office Tel: (212) 263-3156
Fax: (212) 263-7760
E-mail: Jeremy.Nance@med.nyu.edu
Lab Website: http://saturn.med.nyu.edu/research/dg/nancelab/research

Research Theme(s): Cell Polarity, Gastrulation, Organogenesis, Stem Cell Biology
Keywords: Gastrulation, Cell Polarity, Germ Cells, Organogenesis, Morphogenesis

Research Summary:

The overall goal of the lab, which uses C. elegans as a model system, is to understand the molecular basis of morphogenetic events that shape the early embryo.  We are focusing on the mechanisms of gastrulation, which sets apart the germ layers and positions organ primordia; and organogenesis, when organ precursor cells assemble to make a functional organ.  A major focus of our studies is deciphering the mechanisms and contributions of cell polarization during these morphogenetic events.

Two projects in the lab are of particular relevance to understanding the basic biology of stem cells.  In one project, we are studying the mechanisms of contact-induced polarization of very early embryonic cells; the analogous polarization of human blastomeres is believed to help set aside the inner cell mass, which gives rise to the embryo proper and is the source of embryonic stem cells.  In a second project, we are studying the events that allow primordial germ cells to assemble into a functional stem cell niche.

Polarization of early embryonic cells

We have found that a group of conserved cell polarity proteins called PAR proteins is required for the polarization of early embryonic cells. Polarity is induced by cell contact, which forces the local exclusion of PAR proteins (PAR-3, PAR-6, PKC-3), restricting them to contact-free surfaces.  Contact-induced polarity is required for cytoskeletal asymmetries that are important for gastrulation, as described below.

How do cell contacts induce the PAR asymmetries that polarize cells? We identified the PAC-1 protein as a critical regulatory protein that connects cell contact polarization signals to PAR asymmetry.  PAC-1 is a RhoGAP, which negatively regulates Rho GTPases – a family of signaling proteins known for their roles in cell polarization and cytoskeletal organization.  PAC-1 is recruited to sites of cell contact and locally excludes PAR proteins by inhibiting Rho GTPases. We are currently determining how PAC-1 is recruited specifically to cell contacts, and identifying the downstream effectors of PAC-1 and Rho GTPases that regulate PAR protein localization. 

Gastrulation and assembly of the gonad primordium

The animal body plan is organized during the early stages of embryogenesis, when cells that will form internal tissues become positioned in the interior of the embryo. This reorganization, called gastrulation, occurs through the movement of early embryonic cells. During C. elegans gastrulation, specific cells ingress from the surface of the embryo into the interior. Ingressing cells change their shape by constricting their apical surfaces as they enter the embryo during gastrulation. Apical constriction appears to result from a local contraction of the actomyosin cytoskeleton, as non-muscle myosin progressively accumulates at apical surfaces of ingressing cells. When cells fail to develop contact-induced polarity, apical surfaces fail to accumulate non-muscle myosin, these surfaces do not appear to constrict, and ingressions occur slowly.  Therefore one important function for polarization of early embryonic cells is setting up cytoskeletal asymmetries that are important for gastrulation movements.  We are currently investigating how apical constriction and ingression are triggered in specific cell types, and how ingression and cell fate are coupled, ensuring that cells of the proper identity end up in the correct place within the embryo.

We have found that the two primordial germ cells, which are the stem cells that give rise to the entire germ line in the adult, utilize a very different mechanism to ingress during gastrulation.  Germ cells increase their levels of the cell adhesion protein HMR-1 – the worm E-cadherin homolog. HMR-1 is required for germ cells to stick to internal intestinal precursor cells as these cells shift in position and pull the germ cells into the embryo.  In hmr-1 mutants, germ cells detach from intestinal precursors and remain on the surface of the embryo.  Thus in contrast to somatic cells, which generate much of their own force for ingression through apical constriction, germ cells rely on adhesion and forces provided by neighboring cells. 

The gonad forms at the site where the germ cells stop at the end of their ingression.  The two somatic gonad precursor cells migrate to join the two germ cells, forming a four-celled primordial gonad.  To determine how the somatic gonad precursors are guided to the PGCs, we have developed imaging tools to visualize their migration in live embryos.  The primordial gonad serves as a nice model for understanding how stem cells (the germ cells) come together with their niche (the intestinal precursors and somatic gonad precursors) – a poorly understood but critical developmental event.

Polarization of organ precursor cells: forming epithelia

We are also examining the role of PAR proteins in polarizing epithelial cells, which form during organogenesis.  Epithelial cells have a pronounced apicobasal polarity that is important for their function.  Loss of epithelial polarity in humans can also lead to cancer.  We have shown that PAR-3 defines the apical domain of epithelial cells during polarization, and that the PAR-6 protein is required after polarization to assemble the junctions that connect epithelial cells to each other.  Loss of either protein disrupts the formation of epithelial cells and arrests embryos during organogenesis.  We are currently identifying downstream targets of PAR-3 and PAR-6 that are required for these two aspects of epithelial cell formation.

Selected Publications: