The evolution of cell adhesion and signaling mechanisms was essential for the origin of animal multicellularity. These innovations facilitated multicellular development and cell differentiation, and helped resolve the evolutionary conflict between cooperation and competition in single celled organisms. Modern animal development and physiology (including in humans) therefore rests upon a regulatory foundation nucleated by ancient adhesion and signaling mechanisms. Cancer biology is perhaps the most prominent example of how ancient tensions between cell cooperation and competition can re-emerge when fundamental regulatory mechanisms are compromised. By studying choanoflagellates, the closest living single-celled and colony-forming relatives of animals, we aim to determine the minimal molecular toolkit for animal multicellularity. Whole genome and EST sequences from two choanoflagellates, Monosiga brevicollis and Proterospongia, reveal that choanoflagellates express homologs of genes required for cell signaling and adhesion in animals (e.g. receptor tyrosine kinases and cadherins). In addition, Proterospongia develops highly organized colonies in which neighboring cells are connected by cytoplasmic bridges that we hypothesize mediate intercellular signaling and adhesion. Using choanoflagellate-specific molecular, genomic, and cell biological resources generated by my lab, we study choanoflagellate colony formation as a simple model for the evolution and development of animal multicellularity. We propose three aims to determine the mechanisms of intercellular interactions in Proterospongia colonies. First, we will characterize the development and ultrastructure of cytoplasmic bridges and measure their ability to act as intercellular conduits for signaling molecules. Second, we will use proteomic and functional genomic approaches to identify molecules associated with the formation of cytoplasmic bridges. Third, we will investigate the localization and function of choanoflagellate homologs of animal signaling, adhesion, and midbody proteins. By uniting cell biology, functional genomic and biochemical approaches in the study of intercellular interactions in Proterospongia, this research will offer new insights into the molecular underpinnings of animal development and cancer.

Public Health Relevance

Defects in cell adhesion and communication result in a failure of cells to coordinate their behavior properly, and can give rise to catastrophic developmental defects and cancer. The fundamental mechanisms by which animal cells interact may best be studied in the choanoflagellate, an emerging model organism that contains the basic molecular toolkit for animal multicellularity. By reconstructing the ancestry of intercellular interactions, this research aims to provide new insights into animal development, health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM089977-03
Application #
8230816
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$381,285
Indirect Cost
$129,650
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Burkhardt, Pawel; Grønborg, Mads; McDonald, Kent et al. (2014) Evolutionary insights into premetazoan functions of the neuronal protein homer. Mol Biol Evol 31:2342-55
Levin, Tera C; Greaney, Allison J; Wetzel, Laura et al. (2014) The Rosetteless gene controls development in the choanoflagellate S. rosetta. Elife 3:
Levin, Tera C; King, Nicole (2013) Evidence for sex and recombination in the choanoflagellate Salpingoeca rosetta. Curr Biol 23:2176-80
Sebé-Pedrós, Arnau; Burkhardt, Pawel; Sánchez-Pons, Núria et al. (2013) Insights into the origin of metazoan filopodia and microvilli. Mol Biol Evol 30:2013-23
Dayel, Mark J; Alegado, Rosanna A; Fairclough, Stephen R et al. (2011) Cell differentiation and morphogenesis in the colony-forming choanoflagellate Salpingoeca rosetta. Dev Biol 357:73-82
Abedin, Monika; King, Nicole (2010) Diverse evolutionary paths to cell adhesion. Trends Cell Biol 20:734-42
Fairclough, Stephen R; Dayel, Mark J; King, Nicole (2010) Multicellular development in a choanoflagellate. Curr Biol 20:R875-6