Gian Garriga

Professor (Molecular & Cell Biology)

Email: garriga@berkeley.edu

Research areas: Cellular and Molecular Neuroscience, Developmental Neuroscience

To understand how nervous systems develop, we are studying how asymmetric cell division, cell migration and axonal pathfinding contribute to the final form and connectivity of the Caenorhabditis elegans nervous system.

Current Projects

Asymmetric neuroblast divisions. Nervous systems contain many different types of neurons. One way to generate this diversity is for neuroblasts to divide asymmetrically, producing daughter cells that adopt distinct fates. We have identified several proteins that function in several neuroblasts, ensuring that they divide asymmetrically to generate apoptotic cells and neural precursors. The proteins regulate the position of the neuroblast cleavage plane and the distribution of developmental potential to daughter cells. This work has identified two Arf cycles that appear to regulate signaling to these asymmetric dividing neuroblasts. The Arf GAP CNT-2 and ARF-1 act in the dividing neuroblasts, and the Arf GEF GRP-1 and ARF-6 appear to act in cells that tell the neuroblasts to divide asymmetrically. These findings suggest that Arf-mediated trafficking regulates a signal and the ability of the cells to receive or interpret this signal. We are carrying out experiments to identify the signal and understand how it is regulated by Arfs.

Cell and growth cone migrations. Cell migrations shape nervous system structure, and axonal growth cone migrations contribute to nervous system connectivity. While a conserved pathway regulates these migrations along the dorsoventral axis in animals as diverse as C. elegans and mammals, less is known about how migrations along the anterior-posterior (A/P) axis are controlled. We are studying molecules that regulate cell migration and axonal guidance along the C. elegans A/P axis.

Guidance along the A/P axis appears to be regulated by the activity of several guidance cues that interact to control both the direction and final destinations of migrating cells and growth cones. VAB-8L, a novel kinesin-like protein promotes posteriorly directed cell and growth cone migrations. VAB-8L, acting with the conserved Rac exchange factor UNC-73/Trio, increases levels of the SAX-3/Robo guidance receptor to promote posterior migrations, and genetic analysis suggests that VAB-8L and UNC-73 regulate the levels of other guidance receptors. UNC-73 can physically interact with VAB-8L and the intracellular domains of several guidance receptors, suggesting that receptor levels are regulated by direct physical interactions between these molecules. These observations are particularly interesting for two reasons. First, only a handful of conserved cues and receptors appear to guide a myriad of axon projections in developing nervous systems, suggesting that the regulation of these molecules is responsible for the complex axon projection patterns seen in nervous systems. Molecules like VAB-8L may be instrumental in the coordinated regulation of guidance receptors to orchestrate these projection pathways. Second, Rac signaling mediates the effects of guidance receptors. Our results suggest that the situation is more complex, with Racs also regulating the activity of the receptors. We are particularly interested in defining the mechanism of this regulation.

We have also found that Wnts, secreted glycoproteins that function in several different developmental processes, act as guidance cues for the anterior migrations of C. elegans cells and growth cones. The effects of the Wnts are mediated by Frizzled receptors. Wnts and Frizzleds also act to guide growth cones along the mammalian spinal cord, but little is know about how Frizzled receptors transduce their signals in axon guidance. We are particularly interested in defining these intracellular signaling pathways and studying molecules that shape Wnt gradients.
 

Selected Publications

Pan, C. –L., Baum, P.D., Gu, M., Jorgensen, E.M., Clark, S.G. and Garriga, G. (2008). C. elegans AP-2 and retromer control Wnt signaling by regulating MIG-14/Wntless. Developmental Cell 14: 132-139.

Vanderzalm, P. and Garriga, G. (2007). Losing their minds: Mena/VASP/EVL triple knockout mice. Developmental Cell 13: 757-758.

Watari-Goshima, N., Ogura, K., Wolf, F.W., Goshima, Y. and Garriga, G. (2007) C. elegans VAB-8 and UNC-73 regulate the SAX-3 receptor to direct cells and growth cones posteriorly. Nature Neuroscience 10: 169-176.

Cordes, S., Frank, C.A. and Garriga, G. (2006). The C. elegans MELK ortholog PIG-1 kinase regulates cell size asymmetry and daughter cell fate in asymmetric neuroblast divisions. Development 133: 2747-2756.

Pan, C. –L., Endres-Howell, J., Clark, S., Hilliard, M., Cordes, S., Bargmann, C.I. and Garriga, G. (2006). Multiple Wnt homologs regulate anteriorly directed cell and growth cone migrations in C. elegans. Developmental Cell 10: 367-377.

Fleming, T., Wolf, F.W. and Garriga, G. (2005). Sensitized genetic backgrounds reveal a role for C. elegans FGF EGL-17 as a repellent for migrating CAN neurons. Development 132: 4857-4867.

Frank, C. A., Hawkins, N., Guenther, C., Horvitz, H.R. and Garriga, G. (2005). C. elegans HAM-1 positions the cleavage plane and regulates apoptosis in asymmetric neuroblast divisions. Developmental Biology 284: 246-259.

Hawkins, N., Ellis, G. C., Bowerman, B. A. and Garriga, G. (2005). The C. elegans Frizzled MOM-5 regulates the distribution of DSH-2 to control asymmetric cell division. Developmental Biology 284: 301-310.

Forrester, W. C., Kim, C. and Garriga, G. (2004).  The C. elegans Ror RTK CAM-1 inhibits EGL-20/Wnt signaling in cell migration. Genetics 168: 151-162.

Lai, T. and Garriga, G. (2004). The conserved kinase UNC-51 acts with VAB-8 and UNC-14 to regulate posteriorly directed axon outgrowth in C. elegans. Development 131: 5991-6000.

Forrester, W.C., Dell, M., Perens, E. and Garriga, G. (1999). A C. elegans Ror receptor tyrosine kinase regulates cell motility and asymmetric cell division. Nature 400: 881-885.

Wolf, F., Wightman, B., Hung, M. S., Way, J. and Garriga, G. (1998). vab-8 is a key regulator of posteriorly directed migrations in C. elegans and encodes a novel protein with kinesin motor similarity. Neuron 20: 655-666.