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Cell Signaling Pathways – A Case Study Approach L. Emtage, L. Bradbury, N. Coleman, D. Davenport, A. Dunning and J. Grew Signaling and Gene Expression SCF Plasma membrane Kit Grb2 Sos (Ras GEF) (adapter) MI Ras GTP Ras (G protein) GDP RAF (MAPKKK) P MEK (MAPKK) P ERK (MAPK) P C T F BP M ITF P The figure above shows how a series of proteins form a signal transduction pathway. This pathway transmits a cellular signal from the receptor tyrosine kinase (RTK) Kit on the plasma membrane, through the cytoplasm, to the cell nucleus, where it alters gene expression. The Kit protein is expressed in embryonic germ cells (precursors to sperm and eggs), hematopoietic stem cells (blood cell precursors), and melanoblasts. Melanoblasts are the precursors to melanocytes and retinal pigment epithelial (RPE) cells. Melanocytes are found not only in the skin (where they produce the skin coloring pigment melanin), but also in the inner ear, where they help form an important epithelial barrier in the cochlea. Retinal pigment epithelial cells are found in the eye. The transduction molecules GRB2, SOS, Ras, Raf, MEK and ERK are very widely expressed; they may be activated by many different RTKs, and they may activate many different transcription factors. In contrast, the transcription factor MITF is expressed only in melanoblasts. Questions 1. What do you think would be the effect on embryonic development if there was a complete (homozygous) loss of the Kit receptor? A complete loss of SCF? A complete loss of MITF? Complete loss of either the Kit receptor or its ligand SCF (also called KITL or Steel Factor) is lethal due to the inability of the embryo to make blood. All Cell Signaling Pathways – A Case Study Approach L. Emtage, L. Bradbury, N. Coleman, D. Davenport, A. Dunning and J. Grew three cell types listed above are affected in strains carrying milder alleles (mice are anemic, infertile and have pigmentation anomalies). Homozygous severe loss-offunction alleles of MITF leads to complete loss of coat and eye pigmentation, small eyes (due to fate changes in the retinal epithelium that disrupt eye formation), and deafness (Nakayama et al, 1998; Bumsted and Barnstable, 2000). 2. Individuals with Waardenburg syndrome Type 2A often have a white forelock and premature greying, unusual pigmentation of the iris, such as heterochromia iridis, and hearing loss. Waardenburg syndrome is a congenital disorder, caused by dominant loss-of-function mutations in a gene or genes in this pathway. Which gene or genes above could be mutated to give rise to Waardenburg syndrome 2A? Explain your answer. Loss-of-function mutations in MITF are also dominant, and cause either Waardenburg or Tietz albinism-deafness, depending on the severity of the mutation (OMIM, MITF). Neither syndrome is characterized by anemia or infertility, making the possibility of Kit or SCF mutations as a cause seem less likely*. 3. Very pale hair, such as found in Icelanders, is thought to be due in part to a polymorphism in SCF. If you were trying to identify the polymorphism responsible, would you sequence the coding region or the regulatory region of SCF first, and why? Blonde hair is recessive. There are no known recessive mutations in the coding region of SCF that can be homozygous in humans, presumably because homozygous loss-offunction alleles are likely to be lethal (see notes on question #1 above). A SNP (rs12821256), located approximately 350 kb upstream of SCF was found to be associated with blonde (vs brown) hair in Icelanders, confirmed in a sampling of Dutch. The SNP is believed to either modulate SCF expression directly, or to be linked to another polymorphism that affects SCF expression (Sulem et al, 2007). *Although actually, heterozygous loss-of-function mutations in both Kit and SCF have been characterized and neither has the pleiotropic phenotype one might expect! Nakayama, A. et al. 1998. Mutations in microphthalmia, the mouse homolog of the human deafness gene MITF, affect neuroepithelial and neural crest-derived melanocytes differently. Mechanisms of Development, Volume 70, Issues 1–2, Pages 155–166. Bumsted, K.M. and Barnstable, C.J. 2000. Dorsal Retinal Pigment Epithelium Differentiates as Neural Retina in the Microphthalmia (mi/mi) Mouse. Retinal Cell Biology Volume 41, Issue 3 Sulem, P. et al. 2007.Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature Genetics 39, 1443 - 1452