1. Fibroblast Growth Factor 3 (FGF3) int-2
Brandon Williams
3/25/03

2. OBJECTIVES Biochemical Information
Normal Function in Mouse Ear Development
Breast Cancer and FGF3

3. EASY FACTS 22 FGFs in vertebrates FGF3: Chromosome 11 (humans)
Fgf3: Chromosome 7 (mice)
Are secreted polypeptides
Use tyrosine kinase receptors for signaling
Proto-oncogene

4. FUNCTIONS
Cell proliferation, migration, and differentiation during embryonic development
Tissue repair, injury response in adults
Angiogenesis

5. FGF and Tyrosine Kinases
FGFs bind to heparan sulfate and tyrosine kinase receptors (FGFRs)
FGF binds to heparan sulfate
FGF/heparan sulfate dimer binds to a FGFR
Complexes form dimers
Signal transduction

6. FGFRs 7 prototypes from 4 genes
2 or 3 immunoglobulin-like extracellular domains
Heparan sulfate binding domain
Activated through autophosphorylation
Signaling pathway includes Ras, Raf, SOS, etc.

7. Receptor Dimerization

8. FGFRs

9. What Does FGF3 do in a wt Mouse?
Mouse lives (viable)
Inner ear problems
Skeletal problems (tail)

10. Mouse Ear Development FGF3 was thought to induce inner ear development
McKay et al. showed that FGF3 is required for correct development of inner ear, not induction of otic placode

11. Kreisler Mutant Mice
Cannot be maintained as completely homozygous line (females do not breed and repeated outcrossing is needed to produce breeding stud males)
Develop a otic placode etc.
Inner ear is mutant

12. FGF Expression

13. Breast Cancer Numbers
Most frequent cancer among women, other than skin cancer
203,500 new cases per year in U.S.
40,000 die each year
1 in 8 women
5% attributed to mutated BRCA1

14. FGF3 and Breast Cancer Mouse Mammary Tumor Virus (MMTV)
Insertion of MMTV activates several genes including FGF3 that have been associated with breast cancer
Mixed results
Cyclin D is closely linked to FGF3