ZFIN ID: ZDB-PERS-970204-6
Pilgrim, David
Email: dave.pilgrim@ualberta.ca
URL: http://www.biology.ualberta.ca/pilgrim.hp/lab.html
Affiliation: Pilgrim Lab
Address: Department of Biological Sciences CW-405 Biological Sciences Building University of Alberta Edmonton, Alberta, T6G 2E9 Canada
Country: Canada
Phone: (780) 492-2792
Fax: (780) 492-9234

Currently Professor, Department of Biological Sciences, University of Alberta

B.Sc. Biochemistry, Simon Fraser (Vancouver), 1982
Ph.D. Biochemistry, U. Washington (Seattle), 1987
PDF, MRC Laboratory of Molecular Biology, Cambridge, UK

A Précis of Current Research Projects in the Pilgrim Lab

1). Role of the UNC-119 protein in neurogenesis
A major part of our research effort concerns development of the nervous system. C. elegans has an invariant cell lineage, with similar locations and patterns of connectivity of neurons in every animal. Genes required in the nervous system of C. elegans often have subtle mutant phenotypes, affecting behaviours such as response to gentle touch, sensitivity to volatile attractants, contraction of muscles and feeding. One of our projects concerns the unc-119 gene. The behavioural defect in unc-119 mutants lies in at least two aspects; chemosensation and movement. At the cell biological level, it appears that all neuronal growth cones in unc-119 mutants are aberrant, resulting in neurite branching and axonal fasciculation defects. We have identified and isolated UNC-119 homologues from other metazoans (Drosophila, zebrafish, and mammals), these homologues are also neuronally expressed, and, when expressed in C. elegans, these homologues can rescue all aspects of the unc-119 mutant phenotype. Vertebrates we have examined all have two UNC-119 related genes, UNC-119a and UNC-119b. Therefore, we have identified a new family of evolutionarily conserved neuronal proteins. Since most of the other identified components of the C. elegans nervous system have direct human homologues, this work may also shed light on the processes and products involved in the development of the human nervous system. Over the next year we will be using genetic and molecular approaches to identify proteins with which UNC-119 interacts, in C. elegans, Drosophila and humans.
2). UNC-45, a novel myosin interacting protein with distinct roles in muscle and cytokinesis
The Caenorhabditis elegans unc-45 gene is essential for normal thick filament development in body wall muscles. The protein product (UNC-45) contains TPR repeats and has similarity to the yeast She4p protein which is involved in asymmetric segregation of specific mRNAs, but its biochemical function is unknown. UNC-45 differentially co-localizes in body wall muscle thick filaments with myosin heavy chain B (MHC B) but not MHC A. Surprisingly for a gene with muscle phenotype, unc-45 is also maternally contributed and the protein and mRNA are present in all cells of the early embryo. However, zygotic unc-45 expression is only detected in the developing muscle cells. Yeast two-hybrid screens show that UNC-45 interacts with at least two non-muscle myosins, including NMY-2, a type II myosin necessary for asymmetric cell division in C. elegans embryos. UNC-45 and NMY-2 also co-localize in vivo, at the cortex of the cell in early embryos, and localization of UNC-45 is dependent on the presence of NMY-2. Rather than being a muscle-specific protein, this would argue that the UNC-45 protein may have a more general role as a myosin chaperone, stabilizer, or assemblase. We have recently found UNC-45 sequence homologues in Drosophila and humans, and a lethal mutation in the Drosophila gene, leading us to propose that this family of proteins may be an evolutionarily conserved class of myosin interacting proteins.
3). Evolution and functional role of a signal transduction pathway controlling sex determination
C. elegans is proven as a genetic system to study oncogene mediated signal transduction, and we are developing a molecular picture of a signal transduction system involved in sex determination. Although sex is determined in C. elegans by the number of sex (X) chromosomes, mutations have been isolated which cause the animal to completely ignore the chromosomal signal. One such gene is fem-2, which acts at an important branch point in the pathway for the regulation of sex determination in both the soma and germ line. C. elegans are normally hermaphrodites or males, but fem-2 mutants develop as females, regardless of the number of X chromosomes. We have cloned and characterized the fem-2 gene and characterized its product. FEM-2 is a protein phosphatase and is thought to signal between a cell surface receptor (TRA-2) and a nuclear transcription factor (TRA-1). FEM-2 is most similar in its structure to a protein involved in abscisic acid signaling in plants (ABI1), and to a human protein which is a potential regulator of cell death (apoptosis). We have shown that FEM-2 can functionally complement a yeast deficient in PP2C activity, and that the amino terminus of FEM-2 is not necessary for activity in vitro or in vivo . FEM-2 is typical of sex determining genes in many systems in that it is evolving very rapidly. We are presently undertaking a molecular, genetic and cell biological characterization of the fem-2 gene and the interaction of its product with other genes in the pathway. Very recently, we found that FEM-2 expression is controlled at the post-transcriptional level, by a sequence in the 3' UTR, and we are looking for the trans-acting factors which bind there.

Chrystal, P.W., French, C.R., Jean, F., Havrylov, S., van Baarle, S., Peturson, A.M., Xu, P., Crump, J.G., Pilgrim, D.B., Lehmann, O.J., Waskiewicz, A.J. (2021) The Axenfeld-Rieger Syndrome Gene FOXC1 Contributes to Left-Right Patterning. Genes. 12(2):
Prill, K., Carlisle, C., Stannard, M., Windsor Reid, P.J., Pilgrim, D.B. (2019) Myomesin is part of an integrity pathway that responds to sarcomere damage and disease. PLoS One. 14:e0224206
Jean, F., Pilgrim, D. (2019) Evolution and expression of the zebrafish unc119 paralogues indicates a conserved role in cilia. Gene expression patterns : GEP. 33:1-10
Prill, K., Windsor Reid, P., Wohlgemuth, S.L., Pilgrim, D.B. (2015) Still Heart Encodes a Structural HMT, SMYD1b, with Chaperone-Like Function during Fast Muscle Sarcomere Assembly. PLoS One. 10:e0142528
Hansen, L., Comyn, S., Mang, Y., Lind-Thomsen, A., Myhre, L., Jean, F., Eiberg, H., Tommerup, N., Rosenberg, T., Pilgrim, D. (2014) The myosin chaperone UNC45B is involved in lens development and autosomal dominant juvenile cataract.. European journal of human genetics : EJHG. 22(11):1290-7
Crawford, B.D., Po, M.D., Saranyan, P.V., Forsberg, D., Schulz, R., Pilgrim, D.B. (2014) Mmp25β facilitates elongation of sensory neurons during zebrafish development. Genesis (New York, N.Y. : 2000). 52(10):833-48
Myhre, J.L., Pilgrim, D. (2014) A Titan but not Necessarily a Ruler: Assessing the Role of Titin During Thick Filament Patterning and Assembly. Anatomical record (Hoboken, N.J. : 2007). 297:1604-14
Myhre, J.L., Hills, J.A., Jean, F., Pilgrim, D.B. (2014) Unc45b is essential for early myofibrillogenesis and costamere formation in zebrafish. Developmental Biology. 390:26-40
Myhre, J.L., Hills, J.A., Prill, K., Wohlgemuth, S.L., and Pilgrim, D.B. (2014) The titin A-band rod domain is dispensable for initial thick filament assembly in zebrafish. Developmental Biology. 387(1):93-108
Comyn, S.A., and Pilgrim, D. (2012) Lack of Developmental Redundancy between Unc45 Proteins in Zebrafish Muscle Development. PLoS One. 7(11):e48861
Myhre, J.L., and Pilgrim, D.B. (2012) At the Start of the Sarcomere: A Previously Unrecognized Role for Myosin Chaperones and Associated Proteins during Early Myofibrillogenesis. Biochemistry Research International. 2012:712315
Myhre, J.L., and Pilgrim, D.B. (2010) Cellular differentiation in primary cell cultures from single zebrafish embryos as a model for the study of myogenesis. Zebrafish. 7(3):255-266
French, C.R., Erickson, T., French, D.V., Pilgrim, D.B., and Waskiewicz, A.J. (2009) Gdf6a is required for the initiation of dorsal-ventral retinal patterning and lens development. Developmental Biology. 333(1):37-47
Wohlgemuth, S.L., Crawford, B.D., and Pilgrim, D.B. (2007) The myosin co-chaperone UNC-45 is required for skeletal and cardiac muscle function in zebrafish. Developmental Biology. 303(2):483-492
Crawford, B.D., and Pilgrim, D.B. (2005) Ontogeny and regulation of matrix metalloproteinase activity in the zebrafish embryo by in vitro and in vivo zymography. Developmental Biology. 286(2):405-414
Manning, A.G., Crawford, B.D., Waskiewicz, A.J., and Pilgrim, D.B. (2004) UNC-119 homolog required for normal development of the zebrafish nervous system. Genesis (New York, N.Y. : 2000). 40(4):223-230

Altun-Gultekin, Z., Andachi, Y., Tsalik, E., Pilgrim, D., Kohara, Y. and Hobert, O. 2001. A regulatory cascade of three homeobox genes, ceh-10, ttx-3 and ceh-23 , controls cell fate specification of a defined interneuron class in C. elegans. Development, (in press)

Maduro, M.F., Gordon, M., Jacobs, R., and Pilgrim, D.B. 2000. The UNC-119 family of neural proteins is functionally conserved between humans, Drosophila and C. elegans. J. Neurogenetics 13:191-212

Ao, W. and Pilgrim, D.B. 2000. The C. elegans UNC-45 protein is a component of muscle thick filaments and co-localizes with myosin heavy chain B, but not A. J. Cell Biology. 148: 375-384

Cikaluk, D., Tahbaz, N., Hendricks, L. C., DiMattia, G.E., Hansen, D., Pilgrim, D. and Hobman, T. C. 1999 Characterization of GERp95, a membrane-associated protein that belongs to a family of proteins involved in stem cell differentiation. Mol. Biol. Cell 10:3357-3372

Hansen, D. and Pilgrim, D. 1999. Sex and the single worm: sex determination in C. elegans Mechanisms of Development 83:3-15

Venolia, L., Ao, W., Kim, C., Kim, S., Pilgrim, D. 1999. The unc-45 gene of Caenorhabditis elegans encodes a muscle-specific tetratricopeptide repeat-containing protein. Cell Motility and the Cytoskeleton 42:163-177

Locke, J., Podemski, L. , Hanna, S., Hodgetts, R., Pilgrim, D. and Roy, K. 1999. A DNA sequence analysis of the region on Drosophila chromosome 4 around cubitus interruptus reveals two more genes interspersed among repeated sequences. Genome Research 9:137-149

Pilgrim, D. 1998. CeRep25B forms chromosome-specific minisatellite arrays in Caenorhabditis elegans Genome Research 8:1192-1201.

Hansen, D. and Pilgrim, D. 1998. Molecular evolution of a sex determination protein: FEM-2 (PP2C) in Caenorhabditis" . Genetics 149:1353-1362

Ren, P., Lim, C.-S., Johnsen, R., Albert, P., Pilgrim, D., and Riddle, D. 1996. Control of C. elegans larval development by neuronal expression of a TGF-ß homolog. Science 274:1389-1391

Maduro, M., and Pilgrim, D. 1996. Conservation of function and expression of unc-119 from two Caenorhabditis species despite divergence of non-coding DNA. Gene 183:77-85