UMDNJ - ROBERT WOOD JOHNSON MEDICAL SCHOOL
DEPARTMENT OF PATHOLOGY AND LABORATORY MEDICINE

Administrative:

Recruitment Committee for the Molecular Biosciences Graduate Program,
Joint, Rutgers and UMDNJ-RWJMS

Chair, UMDNJ-RWJMS Committee on Graduate Initiatives

Department: Pathology and Laboratory Medicine

Phone Number:

Fax Number: 732-235-4424

Email Address: sotomc@umdnj.edu

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

Many cell divisions require polarized growth.  Healthy mammalian epithelial cells maintain apical basal polarity, while cancerous epithelial cells exhibit defects in the orientation of their division axis.  Cells can divide asymmetrically by partitioning factors to only one of the two daughters.  This may be accomplished intrinsically, or the cell may require a signal from an outside source, like a neighboring cell.  Asymmetrical divisions are often accompanied by a reorientation of the nuclear-centrosomal complex, which results in the mitotic spindle being oriented perpendicular to the previous cleavage axis. 

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.  Since there are few known in vivo targets of CDKs, one exciting avenue for research will be to search for CDK-1 targets required for its polarity function.

 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.

1. Martha C. Soto, Hiroshi Qadota, Katsuhisa Kasuya, Makiko Inoue, Daisuke Tsuboi, Craig C. Mello, and Kozo Kaibuchi.. 2002. The GEX-2 and GEX-3 proteins are required for tissue morphogenesis and cell migrations in C. elegans. Genes &Development 16, p. 620-632
2. 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, p. 113-125.
3. Shin, T.H., Yasuda, J., Rochelaeu, C. E., Lin, R, Soto, M., Bei, Y. Davis, R.J., and C.C. Mello. 1999. MOM-4, a MAP Kinase Kinase Kinase-Related Protein, Activates WRM-1/LIT-1 Kinase to Transduce Anterior/Posteior Polarity Signals in C. elegans. Molecular Cell 4, p. 275-280.
4. Soto, M.C., Chou, Tze-Bin, and Bender, W. 1995. “Comparison of Germline Mosaics of Genes in the Polycomb Group of Drosophila melanogaster,” Genetics 140, p. 231-243.
5. 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.
6. 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, p. 47-55.
7. Christopher C. Quinn, Douglas S. Pfeil, Esteban Chen, Elizabeth L. Stovall, Maegan V. Rivard, Megan K. Gavin, Wayne C. Forrester, Elizabeth F. Ryder, Martha C. Soto, and William G. Wadsworth. (2006). UNC-6/netrin and SLT-1/slit guidance cues orient axon outgrowth mediated by MIG-10/RIAM/Lamellipodin. Current Biology 16, p. 845-853.

8. Hayakawa A, Leonard D, Murphy S, Hayes S, Soto M, Fogarty K, Standley C, Bellve K, Lambright D, Mello C, Corvera S. 2006.  The WD40 and FYVE domain containing protein 2 defines a class of early endosomes necessary for endocytosis.  Proc Natl Acad Sci U S A. 103 (32): 11928. www.pnas.org/cgi/doi/10.1073/pnas.0508832103