Cell movements are critical features of the development of all multicellular organisms, and loss of regulation of regulation of cell movement is an essential step in cancer metastasis. While some progress has been made in identifying cell and substrate adhesion proteins required for some cell movements, how the proteins mediate movement and how the timing of such movements is regulated remains unknown. This proposal focuses on the dramatic migration of six to ten """"""""border cells"""""""" during Drosophila oogenesis as a model system for a genetic dissection of developmentally regulated cell movement. It deals primarily with one gene, slow border cells (slbo), whose function is required for initiation of migration at the proper time. Hypomorphic mutations at this locus cause delayed border cell migration, while stronger alleles cause failure of the migration, suggesting that a threshold level of slbo+ product is required to initiate the migration. A molecular characterization of this gene is proposed, including cloning the locus using existing single P-element insertion alleles, deriving a transcript map for the region, rescuing the mutant phenotype by germline transformation of slbo+ into a mutant background, and determining the deduced amino acid sequence of the slbo product. New alleles will be generated both by excision of transposons currently inserted in the gene and by EMS mutagenesis. DNA sequencing of point mutants will provide structure/function information, and production of antibodies to the protein will allow its subcellular localization and developmental distribution to be determined. Finally, genetic screens are proposed to identify other loci whose products are required for this migration and/or interact with the slbo product.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29GM046425-02
Application #
3468548
Study Section
Genetics Study Section (GEN)
Project Start
1991-08-01
Project End
1996-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Xiang, Wenjuan; Zhang, Dabing; Montell, Denise J (2016) Tousled-like kinase regulates cytokine-mediated communication between cooperating cell types during collective border cell migration. Mol Biol Cell 27:12-9
Cai, Danfeng; Chen, Shann-Ching; Prasad, Mohit et al. (2014) Mechanical feedback through E-cadherin promotes direction sensing during collective cell migration. Cell 157:1146-59
Chang, Yu-Chiuan; Jang, Anna C-C; Lin, Cheng-Han et al. (2013) Castor is required for Hedgehog-dependent cell-fate specification and follicle stem cell maintenance in Drosophila oogenesis. Proc Natl Acad Sci U S A 110:E1734-42
Guo, Qiongyu; Wang, Xiaobo; Tibbitt, Mark W et al. (2012) Light activated cell migration in synthetic extracellular matrices. Biomaterials 33:8040-6
Yoon, Wan Hee; Meinhardt, Hans; Montell, Denise J (2011) miRNA-mediated feedback inhibition of JAK/STAT morphogen signalling establishes a cell fate threshold. Nat Cell Biol 13:1062-9
Wang, Xiaobo; He, Li; Wu, Yi I et al. (2010) Light-mediated activation reveals a key role for Rac in collective guidance of cell movement in vivo. Nat Cell Biol 12:591-7
Lee, T; Feig, L; Montell, D J (1996) Two distinct roles for Ras in a developmentally regulated cell migration. Development 122:409-18
Savant-Bhonsale, S; Montell, D J (1993) torso-like encodes the localized determinant of Drosophila terminal pattern formation. Genes Dev 7:2548-55
Montell, D J; Rorth, P; Spradling, A C (1992) slow border cells, a locus required for a developmentally regulated cell migration during oogenesis, encodes Drosophila C/EBP. Cell 71:51-62
Rorth, P; Montell, D J (1992) Drosophila C/EBP: a tissue-specific DNA-binding protein required for embryonic development. Genes Dev 6:2299-311