Martha C. Soto
Assistant Professor

UMDNJ-RWJMS
Department of Pathology
Room 231
Piscataway. NJ 08854
(732) 235-4424
FAX - 4825
sotomc@umdnj.edu

Visit Dr. Soto's Lab!

Using C. elegans embryos to investigate polarized cell divisions and polarized cell migrations during development

Proper control of cell polarity is essential for all cells. Healthy mammalian epithelial cells maintain apical basal polarity. while cancerous epithelial cells exhibit defects in the orientation of their division axis. Our studies using the nematode C. elegans combine genetic. molecular and biochemical approaches to investigate how specific proteins are used to regulate cell divisions and cell migrations at key points in development. Our lab focuses on two aspects of cell polarity:

We have uncovered a role for the major embryonic cyclin dependent kinase. CDK-1. in controlling the polarity of the EMS division. We found a CDK-1 mutation that affects cell polarity but does not interfere with the cell cycle. CDK-1 therefore has a role in EMS spindle rotation and cell fate. This suggests that cell cycle regulators like CDK-1 are also regulators of polarized cell divisions. perhaps because the decision for how to set up the division axis is best coupled to a specific time in the cell cycle. Genetic experiments have suggested possible targets for CDK-1 in this polarity function. One exciting avenue for research will be to identify the CDK-1 targets that carry out its polarity function. perhaps by regulating cytoskeletal proteins.

(1) How do cell cycle proteins contribute to polarized cell divisions?

In C. elegans embryos signaling between cells begins at the four-cell stage. The P2 cell must be in contact with the EMS cell in order for P2 to send a signal to EMS which induces it to undergo a spindle reorientation and to create two daughters of distinct cells fates. Screens for mutations affecting the fate of EMS have revealed that the polarizing signal from P2 to EMS involves two partially redundant pathways. a wingless(WG/WNT) pathway and another pathway involving the tyrosine kinase SRC-1. One project in the lab focuses on how cell cycle components contribute to the P2 to EMS signal.

 Figure 1: Four cell embryo and the EMS lineage.

Figure 2. Epidermal movements.

GEX proteins and the control of epidermal morphogenesis. Once cells acquire a specific fate. they must undergo cell shape changes and movements to form tissues and organs. The C. elegans epidermis. often referred to as the hypodermis. first forms as a cap of cells on the dorsal side of the embryo (Figure 2.) As soon as the epidermal cells differentiate. they initiate cell shape changes and organize into rows of cells. The cells then migrate to eventually enclose the embryo. The underlying mechanisms that control these events are largely not understood. GEX-2 and GEX-3 are two novel proteins. conserved from worms to humans. which are essential for the earliest movements of the epidermal cells. gex stands for gut on the exterior. the terminal phenotype of mutant embryos. gex genes genetically interact with mutations in the C. elegans homologs of Rac GTPases. Since Rac GTPases are known to regulate actin polymerization. our working hypothesis is that GEX-2 and GEX -3 are regulators of the actin cytoskeleton. In support of this. a third gex gene we cloned. GEX-1. is a homolog of human WAVE1. an activator of the Arp2/3 complex. a 7-protein complex that directly binds actin to promote its polymerization. We are pursuing experiments to test the model that GEX1. GEX-2 and GEX-3 are directly regulating the Arp2/3 complex in order to get cells to change their shape and initiate cell migrations. Further genetic screens will allow us to search for the upstream signals that initiate the cell migrations by regulating GEX-1. GEX-2 and GEX-3.

Selected Publications

Patel FB, Bernadskaya YY, Chen E, Jobanputra A, Pooladi Z, Freeman KL, Gally C, Mohler WA, Soto MC. (2008)The WAVE/SCAR complex promotes polarized cell movements and actin enrichment in epithelia during C. elegans embryogenesis. Dev Biol. 324(2):297-309.

Shakir MA, Jiang K, Struckhoff EC, Demarco RS, Patel FB, Soto MC, Lundquist EA. (2008) The Arp2/3 activators WAVE and WASP have distinct genetic interactions with Rac GTPases in Caenorhabditis elegans axon guidance. Genetics. 179(4):1957-71.

Quinn. CC. Pfeil. DS. Chen. E. Stovall. EL. Rivard. MV. Gavin. MK. Forrester. WC. Ryder. EF. Soto. MC and Wadsworth. WG. (2006). UNC-6/netrin and SLT-1/slit guidance cues orient axon outgrowth mediated by MIG-10/RIAM/Lamellipodin. Current Biology 16:845-853.

Shiriyama. M.. Soto. M.C.. Ishidate. T.. Kim. S.. Nakamura. K.. Bei. Y.. van den Heuvel. S. and Mello. C.C. (2006). The conserved protein kinases CDK-1. GSK-3. KIN-19 and MBK-2 promote OMA-1 destruction to regulate the oocyte-to-embryo transition in C. elegans. Current Biology 16:47-55.

Grigorenko AP. Moliaka YK. Soto MC. Mello CC. Rogaev EI. (2004). The Caenorhabditis elegans IMPAS gene. imp-2. is essential for development and is functionally distinct from related presenilins. Proc Natl Acad Sci 101(41): p. 14955-60.

Soto. MC. Hiroshi Qadota. Kasuya. K. Inoue. M. Tsuboi. D. Mello. CC and Kaibuchi. K. (2002). The GEX-2 and GEX-3 proteins are required for tissue morphogenesis and cell migrations in C. elegans. Genes & Development 16:620-632.

Bei. Y.. Hogan. J.. Berkowitz. L.A.. Soto. M.. Rocheleau. C.E.. Pang. K.M.. Collins. J. and C.C. Mello. (2002). SRC-1 and Wnt signaling act together to specify endoderm and to control cleavage orientation in early C. elegans embryos. Developmental Cell 3:113-125.