The nucleus is highly organized and contains distinct domains, territories and bodies. Intriguingly, the organization of the nucleus varies between cell type and developmental stage. Fetal neuronal cell nuclei, for example, contain Cajal bodies (CBs) and Gems. On the contrary, adult neuronal cells do not contain Gems and the proteins found within this domain localize to CBs. Gems contain the Survival of Motor Neuron (SMN) protein, which is mutated in most patients with the neurodegenerative disorder Spinal Muscular Atrophy. No function for Gems has been described, but current evidence implicates the CB as the site for maturation of ribonucleoproteins (RNPs). Since RNPs are vital for pre- mRNA and pre-rRNA processing, cells actively engaged in transcription (e.g. neuronal and cancer cells) contain prominent CBs. Cancer may induce CB formation, but other diseases may disrupt CB function. Two such diseases are Spinal Muscular Atrophy and Machado-Joseph disease. We hypothesize that the observed developmental diversity in nuclear body organization between different cell types is a manifestation of the most efficient nuclear configuration for RNP biogenesis. We suspect that the post-translational modification status of coilin, the CB marker protein that plays an important role in mammalian cell CB formation and composition, varies with each nuclear configuration. We further hypothesize that diseases which disrupt the functional organization of the nucleus adversely affect RNP maturation, resulting in decreased pre-mRNA splicing. In this application, we propose experiments designed to establish a hierarchy of nuclear organization with respect to nuclear bodies and RNP biogenesis. We will also define the phospho-residues in coilin that are crucial for CB formation, and test if RNP biogenesis is impeded in Machado-Joseph disease. In so doing, we will significantly expand our knowledge of the functional organization of the nucleus in both normal and disease states. ? ?
There is a striking difference in the organization of the nucleus between fetal and adult tissues. We suspect that the protein coilin plays an important role in the formation of two nuclear structures known as Cajal bodies and Gems. Certain diseases, such as cancer and some neurodegenerative disorders, may alter Cajal body and Gem activity. ? ? ?
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