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Functions and Regulation of Nuclear Lamins in Health and Disease

  • Author(s): Jung, Hea Jin
  • Advisor(s): Young, Stephen G
  • et al.
Abstract

Nuclear lamins are intermediate filament proteins that form the nuclear lamina, a structural scaffolding for the nucleus. They interact with other nuclear proteins and the chromatin and are thought to participate in many fundamental cellular pathways. Most vertebrates have two-types of lamins: A-type (lamins A and C) and B-type (lamins B1 and B2). Nuclear lamins, particularly A-type lamins, have attracted considerable attention due to their association with many human genetic diseases. However, despite considerable interest in nuclear lamins, physiologic rationale for the different lamins is unclear. Also, the functional importance of the lamins in the brain has not been thoroughly investigated as the phenotypes of the associated genetic diseases are largely confined to mesenchymal tissues.

In this dissertation, we aimed to better understand distinctive functions and regulation of nuclear lamins in health and diseases, with an emphasis on the brain. In Chapter 2, we showed that prelamin A, but not lamin C, is down-regulated in the brain by a brain-specific microRNA, miR-9 using a series of in vitro studies in cultured cells. In Chapter 3, we generated two new lines of Lmna knock-in mice to investigate whether the regulation of prelamin A by miR-9 is relevant in vivo. These studies, taken together, provided a ready explanation why children with Hutchinson-Gilford progeria syndrome (a progeroid syndrome caused by a mutant form of prelamin A) are spared from neurodegenerative disease: miR-9 selectively eliminates the expression of the culprit molecule—the toxic prelamin A molecule that leads to disease. In Chapter 4, we addressed the physiologic importance of the farnesyl lipid anchor in B-type lamins using knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. In this study, we showed that the farnesyl lipid anchor on lamin B1 is crucial for retaining the nuclear chromatin within the bounds of nuclear lamina during neuronal migration. In Chapter 5, we investigated whether nuclear lamins are essential for proliferation and differentiation of non-neuronal cells in vivo using keratinocyte-specific Lmna/Lmnb1/Lmnb2 triple-knockout mice.

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