A wide variety of cellular processes, including fertilization, cell division, cell migration, and cell polarity, depend on nuclear migration events. Inner nuclear membrane SUN proteins and outer nuclear membrane KASH proteins couple nuclei to the cytoskeleton. Gaps remain in understanding how KASH-SUN bridges are formed and function. Specifically, the molecular mechanisms of how proteins are trafficked to the inner nuclear mem- brane, how microtubules and motors are coordinated to move nuclei, and how KASH and SUN proteins interact to connect cytoplasmic forces to nuclei remain unknown. Our hypothesis is that forces generated by microtubule motors in the cytoplasm are connected to the nucleus by a bridge of conserved KASH and SUN proteins. Understanding how forces are transferred across the nuclear envelope will allow us to elucidate mechanisms of how nuclei are positioned in a cell, how chromosomes are moved inside the nucleus, and how perturbations of these processes disrupt cell and developmental processes. Our model will be tested by three specific aims:
(Aim 1) Elucidate mechanisms of inner nuclear membrane biogenesis. The current paradigm is that membrane proteins diffuse within the ER membrane to the nuclear envelope. Our preliminary data support an alternative active transport model for inner nuclear membrane trafficking, using a combination of the soluble nuclear import machinery, membrane-bound importins, and a Golgi trafficking intermediate. We hypothesize that multiple inner-nuclear-membrane-localization signals function to first actively transport UNC-84 from the peripheral ER to the nuclear envelope and to then mediate movement across the nuclear pore.
(Aim 2) Deter- mine how kinesin, dynein, and microtubules function to move nuclei. Tug-of-war, interdependent regulation, and bi-directional movement are proposed models to explain how motors of opposite polarity function together to move a cargo. Our hypothesis is that kinesin-1 provides the force to move nuclei and that dynein mediates backwards movements and rolling to bypass roadblocks. We will distinguish between two models for how NOCA-1 regulates polarized microtubule arrays-by regulating either plus-end tip dynamics or nucleation of microtubules.
(Aim 3) Determine how forces generated in the cytoplasm are coupled to the nucleus. Two models could explain the role of the KASH-SUN bridge in nuclear migration;they could serve simply as outer nuclear docking sites or, also as transducers of force across the nuclear envelope. We hypothesize that forces generated in the cytoplasm are directly linked to the nuclear lamina by KASH-SUN bridges. Our approach is innovative because it takes advantage of a C. elegans model with unique genetic and molecular strengths with the ability to film and quantify nuclear migration. The proposed research is significant because it is expected to (A) elucidate mechanisms of protein transport to the inner nuclear membrane, (B) elucidate mechanisms of bi- directional nuclear migration along polarized microtubules that will be applicable to other large cargos, and (C) determine how the forces that move nuclei are transferred across the nuclear envelope.

Public Health Relevance

The proposed research is relevant to public health because mutations in KASH and SUN proteins have been shown to cause or to be linked to muscular dystrophies, ataxias, lissencephaly, progeria, and multiple cancers. Moreover, defects in nuclear migration contribute to many of the neuromuscular defects of these diseases. Thus, the proposed research is relevant to the part of the NIH's mission that fosters fundamental discoveries in basic cell and developmental biology with great potential for a positive impact on human health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Nie, Zhongzhen
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University of California Davis
Anatomy/Cell Biology
Schools of Medicine
United States
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Fridolfsson, Heidi N; Herrera, Leslie A; Brandt, James N et al. (2018) Genetic Analysis of Nuclear Migration and Anchorage to Study LINC Complexes During Development of Caenorhabditis elegans. Methods Mol Biol 1840:163-180
Herrera, Leslie A; Starr, Daniel A (2018) The E3 Ubiquitin Ligase MIB-1 Is Necessary To Form the Nuclear Halo in Caenorhabditis elegans Sperm. G3 (Bethesda) 8:2465-2470
Cain, Natalie E; Jahed, Zeinab; Schoenhofen, Amy et al. (2018) Conserved SUN-KASH Interfaces Mediate LINC Complex-Dependent Nuclear Movement and Positioning. Curr Biol 28:3086-3097.e4
Starr, Daniel A (2017) Muscle Development: Nucleating Microtubules at the Nuclear Envelope. Curr Biol 27:R1071-R1073
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
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

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