The position of the nucleus is carefully controlled in a wide variety of cell types. Nuclear migration plays a role in normal cell migration events and metastasis;defects in nuclear migration lead to the neurological disease Lissencephaly. Nuclear anchorage functions in the development of the neuro-muscular junction and may contribute to muscular dystrophy. A group of three conserved nuclear envelope proteins are required for proper nuclear positioning in C. elegans. Our objective is to characterize how these proteins function to control nuclear positioning and to identify other proteins that function with or in parallel to them. Our central hypothesis is that UNC-84 functions at the inner nuclear membrane to recruit UNC-83 and ANC-1 to the outer nuclear membrane. Together, they bridge the nuclear envelope to connect the nuclear matrix to the cytoskeleton.
Our first aim will determine the topology of these three proteins using an in vivo protease protection assay and immuno-EM.
Aim 2 will use molecular genetic techniques to test the central link of our model, the interaction between the SUN domain of UNC-84 and the KASH domains of UNC-83 and ANC-1.
In aim 3 we expect to link UNC-83 to the cytoskeleton by identifying interacting partners through biochemical and molecular screens using essential portions of the novel domain of UNC-83.
In aim 4 we take a genetic approach to identify additional proteins involved in nuclear positioning by cloning existing enhancer of unc-83 or unc-84 alleles. We will use genome-wide RNAi to screen for more enhancers. The ability to combine genetic, biochemical, and molecular approaches in a developmental system makes C, elegans a powerful system for these studies. Together, these studies will provide mechanistic insight into the fundamental problem of how the nucleus positions itself in the cytoplasm.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073874-05
Application #
7753869
Study Section
Cell Structure and Function (CSF)
Program Officer
Deatherage, James F
Project Start
2006-01-01
Project End
2011-09-29
Budget Start
2010-01-01
Budget End
2011-09-29
Support Year
5
Fiscal Year
2010
Total Cost
$249,166
Indirect Cost
Name
University of California Davis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Starr, Daniel A; Rose, Lesilee S (2017) TorsinA regulates the LINC to moving nuclei. J Cell Biol 216:543-545
Lawrence, Katherine S; Tapley, Erin C; Cruz, Victor E et al. (2016) LINC complexes promote homologous recombination in part through inhibition of nonhomologous end joining. J Cell Biol 215:801-821
Bone, Courtney R; Starr, Daniel A (2016) Nuclear migration events throughout development. J Cell Sci 129:1951-61
Bone, Courtney R; Chang, Yu-Tai; Cain, Natalie E et al. (2016) Nuclei migrate through constricted spaces using microtubule motors and actin networks in C. elegans hypodermal cells. Development 143:4193-4202
Cain, Natalie E; Starr, Daniel A (2015) SUN proteins and nuclear envelope spacing. Nucleus 6:2-7
Zhou, Yuning; Wang, Qingding; Weiss, Heidi L et al. (2014) Nuclear factor of activated T-cells 5 increases intestinal goblet cell differentiation through an mTOR/Notch signaling pathway. Mol Biol Cell 25:2882-90
Bone, Courtney R; Tapley, Erin C; Gorjánácz, Mátyás et al. (2014) The Caenorhabditis elegans SUN protein UNC-84 interacts with lamin to transfer forces from the cytoplasm to the nucleoskeleton during nuclear migration. Mol Biol Cell 25:2853-65
Cain, Natalie E; Tapley, Erin C; McDonald, Kent L et al. (2014) The SUN protein UNC-84 is required only in force-bearing cells to maintain nuclear envelope architecture. J Cell Biol 206:163-72
Luxton, G W Gant; Starr, Daniel A (2014) KASHing up with the nucleus: novel functional roles of KASH proteins at the cytoplasmic surface of the nucleus. Curr Opin Cell Biol 28:69-75
Chang, Yu-Tai; Dranow, Daniel; Kuhn, Jonathan et al. (2013) toca-1 is in a novel pathway that functions in parallel with a SUN-KASH nuclear envelope bridge to move nuclei in Caenorhabditis elegans. Genetics 193:187-200

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