Robert H. Blelloch
| Years in MSTP | 1992-2001 |
| PhD | Biochemistry, 1999 |
| Mentor | Judith Kimble |
| Thesis |
Control of Organ Shape by the GON-1 Metalloprotease |
| Residency |
Pathology, Brigham and Women's Hospital |
| Fellowship |
Stem cell biology, MIT |
| Investigative Research | Control of stem cell fate by SiRNAs |
| Current Position | Assistant professor, Stem Cell Program, Department of Urology, University of California-San Francisco |
Thesis Abstract
Development of the C. elegans gonad involves several morphogenetic processes. First is arm extension, which is controlled by the gonadal leader cells (distal tip cell, DTC, in hermaphrodites). Second is formation of the somatic gonadal primordium (SGP), which involves coalescence of somatic gonadal precursor cells into a prepattern of the adult gonad. Third is transformation of the SGP and its descendants into the complex tubular organs (e.g. uterus, spermatheca) of the adult gonad.
The gon-1 gene is required for all three processes: gon-1 null mutants do not extend gonadal arms, do not form an SGP and do not generate organized tubular structures. However, cell lineage patterns are unaffected in gon-1 mutants and tissue differentiation occurs normally. Laser ablation of the leader cells in wild-type animals phenocopies gon-1, although the effects are less severe. Therefore, many, but not all, of the gonadal defects in gon-1 mutants can be ascribed to a loss of leader cell function.
The gon-1 gene encodes a protein containing a metalloproteinase domain followed by numerous thrombospondin type-1 repeats. It belongs to a small gene family that includes the bovine procollagen I N-proteinase. An E > A mutation in the metalloproteinase active site abolishes GON-1 function. A gon-1 promoter fusion, gon-1 5'::GFP, drives expression in leader cells and in muscle cells.
When the gon-1 coding region is placed under control of a DTC promoter (lag-2::GON-1) and is expressed in gon-1(null) mutant hermaphrodites, the gonadal arms extend as in wild-type along a proximal-distal axis. Expression from a muscle promoter, on the other hand, promotes gonadal expansion along all axes.
I postulate that gon-1 is normally expressed in the leader cells to direct proximal-distal extension of the gonadal arms and in muscle cells to achieve the dorsal-ventral and left-right expansion of the gonad. I also suggest that the GON-1 metalloprotease achieves these ends by remodeling the basement membrane to permit and direct gonadal growth.
Publications
Mathies LD, Schvarzstein M, Morphy KM, Blelloch R, Spence AM, Kimble J. 2004. TRA-1/GLI controls development of somatic gonadal precursors in C. elegans. Development. 131:4333-43.
Blelloch R, Anna-Arriola SS, Gao D, Li Y, Hodgkin J, Kimble J. 1999. The gon-1 gene is required for gonadal morphogenesis in Caenorhabditis elegans. Dev Biol 216:382-93.
Blelloch R, Newman C, Kimble J. 1999. Control of cell migration during Caenorhabditis elegans development (review). Curr Opin Cell Biol 11:608-13.
Blelloch R, Kimble J. 1999. Control of organ shape by a secreted metalloprotease in the nematode Caenorhabditis elegans. Nature 399:586-90.
Roehl H, Bosenberg M, Blelloch R, Kimble J. 1996. Roles of the RAM and ANK domains in signaling by the C. elegans GLP-1 receptor. EMBO J 15:7002-12. PMCID: 452526
Reznikoff CA, Belair CD, Yeager TR, Savelieva E, Blelloch RH, Puthenveettil JA, Cuthill S. 1996.
A molecular genetic model of human bladder cancer pathogenesis (review). Semin Oncol 23:571-84.