Presented at Cardiology 2011, 15th Annual Update on Pediatric and Congenital Cardiovascular Disease.

5. Nf1 -/- embryos die of cardiovascular failure Jacks T. et al., Nat Gen 1994

7. Nf1 -/- hearts have a lethal series of defects wild type e13.5 Nf1 -/- e13.5 Gitler, et al., Nat Gen 2003

8. Disease-causing mutations occur throughout NF1 … but only the NF1 G AP- R elated D omain (GRD) has a well-described function

9. NF1 GRD downregulates activated Ras Ismat et al., JCI 2006

11. GRD expression rescues Nf1 -/- embryonic heart defects NF1 GRD expression rescues pericardial effusion ( ), enlarged endocardial cushion ( arrows ), and myocardial thinning (arrowheads). * Ismat et al., JCI 2006

12. GRD rescued Nf1 -/- mice die soon after birth Genotype Mendelian Expected Observed * All rescued Nf1 -/- mice died on the first postpartum day. Ismat et al., JCI 2006 Nf1 +/+ 13 17 27 Nf1 +/+ , GRD k/+ 13 17 13 Nf1 +/+ , CMV-cre + 13 17 15 Nf1 +/+ , GRD k/+ , CMV-cre + 13 17 17 Nf1 +/- 26 35 22 Nf1 +/- , GRD k/+ 26 35 40 Nf1 +/- , CMV-cre + 26 35 37 Nf1 +/- , GRD k/+ , CMV-cre + 26 35 32 Nf1 -/- 13 0 0 Nf1 -/- , GRD k/+ 13 0 0 Nf1 -/- , CMV-cre + 13 0 0 Nf1 -/- , GRD k/+ , CMV-cre + 13 0 5*

13. Late mortality in Nf1 myocardial knockout n=23 n=20

14. Progressive cardiac hypertrophy & fibrosis in Nf1 mKO

15. Cardiac dilation & reduced shortening in Nf1 mKO

16. Rescue of Nf1 mKO cardiac hypertrophy with NF1 GRD

17. Hypertrophic occlusive vasculopathy in NF1 Kanter et al., J Peds 2006

18. “ Normal” arteries in Nf1 smooth muscle knock-out ( Nf1 smKO) No anatomical differences seen in elastin ( A , B ) and smooth muscle α - actin staining ( C , D ) between wild type and Nf1 smKO arteries. Xu & Ismat et al., Circ 2007

19. Elevated blood pressures in Nf1 smKO mice Junwang Xu & Tao Wang

20. Nf1 smKO injury-induced intimal hyperplasia rescued by GRD Xu & Ismat et al., Circ 2007

23. Tidyman & Rauen Current Opinion in Genetics & Development 2009, 19:230–236 (PTPN11)

24. Acknowledgements Past support: a Young Investigator Award from the Children’s Tumor Foundation , a Physician Scientist Development Award (K08) from the NHLBI ; Current support: a Basil O’Connor scholarship from the March of Dimes Foundation , a cardiovascular research grant from the W.W. Smith Charitable Trust , and grants from the CHOP Cardiac Center Scientific Review Committee . Ismat Lab Almedia McCoy Timothy Macatee MCRC Core Facilities Histology Core (MM Lu) Transgenic Core (D Zhu) Physiology Core (T Wang*) Penn Core Facilities Flow Cytometry & Cell Sorting Small Animal Imaging Microarray Core Facility Collaborators & Others Jonathan Epstein (Penn) Aaron Gitler (Penn) Elizabeth Goldmuntz (CHOP) Tyler Jacks (MIT) Maria Kontardis (BIDH-HMS) Thomas Look (DFCI) Arun Padmanabhan (Penn) Luis Parada (UTSW) Nancy Ratner (Cincinnati) Xin Zhang (IUPUI) Yuan Zhu (Michigan)