This is a renewal application to continue work using gene targeting and other modern molecular and genetic methods to study the developmental regulation of early mammalian development. Emphasis will be placed on the 413.d insertional mutation and on the role of several bone morphogenetic proteins (BMP), BMP-5, BMP-6 and BMP-7. 413.d appears to control mesoderm formation in part because expression is restricted to cells surrounding the anterior tip of the primitive streak (i.e., Hensen's node, blastopore lip) and because mutant mice fail to form mesoderm. BMP proteins are an important sub-family in the TGF-beta family of genes. This large family has overlapping expression patterns and presumably overlapping functions. They are thought to be involved in inductive processes and some are involved in dorso-ventral patterning. By using a combination of knock-out mutations, molecular markers for cells and proteins, complementation with spontaneous mutations, reporter gene constructs, and other strategies, the applicant proposes comprehensive studies of the function of genes that regulate early stages of embryonic development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD025208-08
Application #
2199437
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1989-01-01
Project End
1998-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
8
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Kim, R Y; Robertson, E J; Solloway, M J (2001) Bmp6 and Bmp7 are required for cushion formation and septation in the developing mouse heart. Dev Biol 235:449-66
Solloway, M J; Robertson, E J (1999) Early embryonic lethality in Bmp5;Bmp7 double mutant mice suggests functional redundancy within the 60A subgroup. Development 126:1753-68
Waldrip, W R; Bikoff, E K; Hoodless, P A et al. (1998) Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell 92:797-808
Varlet, I; Collignon, J; Robertson, E J (1997) nodal expression in the primitive endoderm is required for specification of the anterior axis during mouse gastrulation. Development 124:1033-44
Varlet, I; Collignon, J; Norris, D P et al. (1997) Nodal signaling and axis formation in the mouse. Cold Spring Harb Symp Quant Biol 62:105-13
Ioffe, E; Liu, Y; Bhaumik, M et al. (1995) WW6: an embryonic stem cell line with an inert genetic marker that can be traced in chimeras. Proc Natl Acad Sci U S A 92:7357-61
Poirier, F; Robertson, E J (1993) Normal development of mice carrying a null mutation in the gene encoding the L14 S-type lectin. Development 119:1229-36
Schwartzberg, P L; Robertson, E J; Goff, S P (1990) Targeted gene disruption of the endogenous c-abl locus by homologous recombination with DNA encoding a selectable fusion protein. Proc Natl Acad Sci U S A 87:3210-4
Charron, J; Malynn, B A; Robertson, E J et al. (1990) High-frequency disruption of the N-myc gene in embryonic stem and pre-B cell lines by homologous recombination. Mol Cell Biol 10:1799-804
Schwartzberg, P L; Goff, S P; Robertson, E J (1989) Germ-line transmission of a c-abl mutation produced by targeted gene disruption in ES cells. Science 246:799-803