Till mina finaste! Faculty opponent Catharina Larsson, Professor, M.D. Karolinska Institute Stockholm, Sweden Examining committee Helena Jernberg-Wiklund, Professor Uppsala University Uppsala, Sweden Mikael Lindström, Associate Professor Karolinska Institute Stockholm, Sweden Gunnar Schulte, Associate Professor Karolinska Institute Stockholm, Sweden Chairman Larry Mansouri, Ph.D. Uppsala University Uppsala, Sweden Supervisors Niklas Dahl, Professor, M.D Jens Schuster, Ph.D. Uppsala University Uppsala, Sweden List of Papers This thesis is based on the following papers, which are referred to in the text by their corresponding Roman numerals (I-IV). I Fröjmark, AS., Badhai, J., Klar, J., Thuveson, M., Schuster, J., Dahl, N. (2009) Cooperative effect of ribosomal protein s19 and Pim-1 kinase on murine c-Myc expression and myelo- id/erythroid cellularity. Journal of Molecular Medicine, 88(1):39–46 II Badhai, J., Fröjmark, AS., Davey, E., Schuster, J., Dahl, N. (2009) Ribosomal protein S19 and S24 insufficiency cause dis- tinct cell cycle defects in Diamond-Blackfan anemia. Biochimi- ca et Biophysica Acta - Molecular Basis of Disease, 1792(10):1036-42 III Schuster, J., Fröjmark, AS., Nilsson, P., Badhai, J., Virtanen, A., Dahl, N. (2010) Ribosomal protein S19 binds to its own mRNA with reduced affinity in Diamond-Blackfan anemia. Blood cells, Molecules, and Diseases, 45(1):23-28 IV Fröjmark, AS., Schuster, J*., Entesarian, M*., Sobol, M., Na- waz, S., Baig, SM., Klar, J., Dahl, N. Mutations in Frizzled 6 (FZD6) cause isolated autosomal recessive nail dysplasia. Manuscript *These authors contributed equally to the work. Reprints were made with permission from the respective publishers. Contents Introduction ................................................................................................... 13 Genetic variation ...................................................................................... 13 Cell cycle .................................................................................................. 14 Apoptosis .................................................................................................. 15 Ribosomes and ribosomal biogenesis ....................................................... 17 Ribosomopathies ................................................................................. 19 Ribosomopathies and predisposition to malignancies ......................... 20 Hematopoiesis .......................................................................................... 20 Erythropoiesis ...................................................................................... 21 Diamond-Blackfan Anemia .......................................................................... 24 Diagnosis and clinical description ............................................................ 24 Treatment ................................................................................................. 24 Genetic studies ......................................................................................... 25 Genotype-phenotype correlation ......................................................... 25 Defective erythropoiesis in DBA ............................................................. 25 Hypothesizes and model systems ............................................................. 26 Ribosomal Stress Hypothesis .............................................................. 27 Translational Defect Hypothesis .......................................................... 27 Nail dysplasia ................................................................................................ 29 Embryonic development .......................................................................... 29 Limb development ............................................................................... 30 Nail development ................................................................................. 32 FZD/WNT signaling ................................................................................ 32 WNT/β-catenin pathway ...................................................................... 33 WNT/JNK pathway ............................................................................. 34 WNT/Ca2+ pathway ............................................................................. 35 Present investigations.................................................................................... 36 Aims ......................................................................................................... 36 Methods .................................................................................................... 36 Mouse models ...................................................................................... 38 Results and discussion .............................................................................. 38 Paper I. Cooperative effect of ribosomal protein s19 and Pim-1 kinase on murine c-Myc expression and myeloid/erythroid cellularity. ......... 38 Paper II. Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond-Blackfan anemia .................................. 41 Paper III. Ribosomal protein S19 binds to its own mRNA with reduced affinity in Diamond-Blackfan anemia. ................................................ 42 Paper IV. Mutations in Frizzled 6 (FZD6) cause isolated autosomal recessive nail dysplasia. ....................................................................... 43 Concluding remarks and future perspectives ................................................ 46 Diamond-Blackfan Anemia ...................................................................... 46 Nail dysplasia ........................................................................................... 49 Acknowledgements ....................................................................................... 51 References ..................................................................................................... 53