Nuclear Migration and Anchorage.  The position of the nucleus within a cell is important to the growth and function of a wide variety of cell types. Understanding the mechanisms controlling nuclear migration and positioning is central to our understanding of animal development. Our analyses of three genes, unc-83, unc-84, and anc-1, have uncovered novel, but likely conserved mechanisms, at the nuclear envelope required for nuclear anchorage and migration (collaborated with R. Horvitz and two other laboratories).  Our studies suggest that UNC-84 is a nuclear envelope protein that uses its conserved SUN domain to recruit UNC-83 and ANC-1 to the nuclear envelope for migration and anchorage, respectively.  ANC-1, a huge protein, mediates nuclear anchorage by connecting the nuclear envelope to actin cytoskeleton.
    To study a similar nuclear positioning mechanism in mammals. We have recently collaborated with Mark Grady and Joshua Sanes at the Washington University, St. Louis to study the role of syne proteins, which are homologous to ANC-1 in some key structural features, in mouse muscle cells. Sanes group has previously shown that nuclei aggregated under the neuromuscular junctions (NMJ) have high amounts of Syne-1 at their nuclear envelope. We have observed that expressing dominant-negative form of syne-1 in a transgen driven by a muscle specific promoter prevents nuclei from clustering under NMJ. Our other collaborators at Fudan Institute of Developmental Biology and Molecular Medicine are creating deletion mutations in both syne genes as well two SUN domain genes in mice for further analysis of the mechanism.

IV. Fatty acid functions and homeostasis

Fatty Acids (FA) are components of a large variety of lipid molecules that play essential roles in nearly all biological processes. The maintenance of proper levels and ratios between different FA molecules is expected to be extremely important for their roles in cellular functions. Steered by our previous study on genes involved in human macular dystrophy, we have recently applied C. elegans genetics, gas chromatography, and DNA microarray technology to study the function FA elongation enzymes in regulation of FA biosynthesis.  In our most recent study, we elucidated the roles of two elongases, ELO-5 and ELO-6, and a predicted branched-chain -keto-acid dehydrogenase in the biosynthesis of two mmBCFA, C15ISO and C17ISO. We have shown that these mmBCFA are essential for C. elegans growth and development,  for the suppression of mmBCFA biosynthesis results in a full arrest of animals at the first larval stage. This arrest is reversible and can be overcome by feeding the arrested animals with mmBCFA supplements. We also show that not only do the levels of C15ISO and C17ISO affect the expression of several genes, but also some of these genes regulate biosynthesis of mmBCFA, suggesting potential feedback regulation. This study exposes unexpected and crucial physiological functions of C15/C17ISO in C. elegans and suggests a potentially important role for mmBCFA in other eukaryotes.

PUBLICATIONS:


From Last Century.

Han M. Ras proteins in developmental pattern formation in Caenorhabditis elegans and Drosophila. [Review]] Seminars in Cancer Biology. 3(4):219-28, 1992 Aug. Abstract
Han M. Golden A. Han Y. Sternberg PW. C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation. Nature. 363(6425):133-40, 1993 May 13. Abstract
Sternberg PW. Golden A. Han M. Role of a raf proto-oncogene during Caenorhabditis elegans vulval development. Philosophical Transactions of the Royal Society of London - Series B: Biological Sciences. 340(1293):259-65, 1993 Jun 29.Abstract
Han, M. (1993). Ras-mediated signaling pathway during vulval development in C. elegans. Ciba Foundation symposium 176. The GTPase superfamily. pp. 215-217.
Han, M. (1994). Common themes in different lives. Book Review on Signal Transduction- Prokaryotic and Simple Eukaryotic Systems. Bioessays 16, 445-446.
Sternberg, P. and M. Han. (1994) Let-60 ras. Guidebook to the small GTPases. (Eds., L.A. Huber, M. Zerial and J. Tooze).
Wu Y. Han M. Suppression of activated Let-60 ras protein defines a role of Caenorhabditis elegans Sur-1 MAP kinase in vulval differentiation. Genes & Development. 8(2):147-59, 1994 Jan.  Abstract
Wu Y. Han M. Guan KL. MEK-2, a Caenorhabditis elegans MAP kinase kinase, functions in Ras-mediated vulval induction and other developmental events. Genes & Development. 9(6):742-55, 1995 Mar 15.  Abstract
Hara M. Han M. Ras farnesyltransferase inhibitors suppress the phenotype resulting from an activated ras mutation in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America. 92(8):3333-7, 1995 Apr 11.  Abstract
Singh N. Han M. sur-2, a novel gene, functions late in the let-60 ras-mediated signaling pathway during Caenorhabditis elegans vulval induction. Genes & Development. 9(18):2251-65, 1995 Sep 15.  Abstract
Sundaram M. Han M. The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction . Cell. 83(6):889-901, 1995 Dec 15. Abstract
Sundaram M. Han M. Control and integration of cell signaling pathways during C. elegans vulval development. [Review] Bioessays. 18(6):473-80, 1996 Jun.
Sundaram M. Yochem J. Han M. A Ras-mediated signal transduction pathway is involved in the control of sex myoblast migration in Caenorhabditis elegans. Development. 122(9):2823-33, 1996 Sep. Abstract
Han M. and M. Sundaram (1996) Ras-mediated signal transduction pathway in C. elegans. In: Regulation of the Ras Signaling Network (H. Maruta, ed.). R.G. Landes Company, pp. 47-74.
Zhang, K., Yen, H., Han, M. & Donoso, L. A. (1996) Molecular genetics of inherited macular dystrophies. British Journal of Ophthalmology. 80(11):1018-1022, 1996 Nov.
Yochem J. Sundaram M. Han M. Ras is required for a limited number of cell fates and not for general proliferation in Caenorhabditis elegans. Molecular and Cellular Biology. 17(5):2716-2722, 1997 May. Abstract
Han M. Gut Reaction to Wnt Signaling in Worms. Cell. 90(4):581-584, 1997 Aug 22. Abstract
Sugimoto, T., Stewart, S., Han, M. and Guan, K-L (1997). The kinase suppressor of Ras (KSR) uncouples Elk-1 phosphorylation from MAP kinase activation. EMBO J17, 1717-1727.
Dent, J. and Han, M. (1998). Post-embryonic expression pattern of C. elegans let-60 ras reporter constructs.  Mechanisms of Development.72, 179-182. Abstract
Gu, T. and Han, M. (1998) The C. elegans sur-5 gene negatively regulates let-60 ras activity and encodes an novel but evolutionarily conserved ATP binding protein. Mol. Cell. Biol.,18(8):4556-4564.
Kniazeva, M, Han, M. (1998). Addition of a second primer in PCR mixture after the first step of initial denaturation greatly improves synthesis of specific PCR fragments. TTO#1416, Elsevier Trends J., 1998
Yochem, J., Gu, T. and Han, M. (1998) Usage of SUR-5-GFP fusion protein as a marker to rapid DNA-mediated transformation and mosaic analysis in C. elegans. Genetics,149:1323-1334. Abstract
Sieburth, D., Qun, S., and Han, M.(1998) SUR-8,a Conserved Ras-Binding Protein with Leucine-Rich Repeats, Positively Regulates Ras-Mediated Signaling in C.elegans. Cell. 94 (1):119-130. Abstract
Sternberg, P. and Han, M. (1998). Genetics of Ras Siganling in Caenorhabditis elegans. Trends in Genetics, 14 (11): 466-472. Abstract
Fay, D. S., Stanley, H., Han, M. and Wood, W. B. (1999) A Caenorhabditiselegans Homologue of hunchback is Required for Late Stages of Development but Not Early Embryonic Patterning.  Dev. Biol. 205, 204-253. Abstract
Hanna-Rose, W. and Han, M. (1999). Cog-2, a Sox domain protein necessary for establishing the functional connection between the uterus and the vulva in Caenorhabditis elegans. Development. 126 (1), 169-179. Abstract
Yochem, J. Tuch, S., Greenwald, I. and Han, M. (1999) A gp330/megalin-related protein is required in the major epidermis of Caenorhabditis elegans for completion of molting. Development. 126 (3), 597-606. Abstract
Malone, C. J., Fixen, W. D., Horvits, H. R. and Han, M. (1999) UNC-84 localizes to the nuclear envelope and is required for nuclear migration and anchoring during C. elegans development. Development. 126, 3171-3181.
Kniazeva, M., Zawistovski, J., Han, M. (1998). Addition of a second primer in PCR mixture after the first step of initial denaturation greatly improves synthesis of specific PCR fragments. TTO#1416, Elsevier Trends Journals, 1998.
Zhang K, Garibaldi DC, Kniazeva M, Albini T, Chiang MF, Kerrigan M, Sunness JS, Han M, Allikmets R. (1999). A novel mutation in the ABCR gene in four patients with autosomal recessive Stargardt disease. Am J Ophthalmol. 128:720-4
Kniazeva, M., Chiang, M. F., Cutting, G. R.,  Han, M., Zhang, K. (1999) Clinical and genetic studies of an autosomal dominant cone-rod dystrophy with features of Stargardts disease. Ophthalmic Genetics 20, 71-81. Abstract
Kniazeva, M., Chiang, M. F., Han, M., Zhang, K. (1999)  A new gene forautosomal dominant Stargardt-like disease maps to chromosome 4. Amer. J. Hum. Gen. 64, 1394-1399.
Zhang K, Kniazeva M, Han M., Dean M, Allikmets R.  The ABCR Gene in Recessive and Dominant Stargardt Disease: A genetic Pathway in Macular Degeneration.  Genomics, 60(2):234-237, 1999.


2000

Kniazeva M, Traboulsi EI, Yu Z, Stefko ST, Gorin MB, Shugart YY, O'Connell JR, Blaschak CJ, Cutting G, Han M, Zhang K. (2000). A new locus for dominant drusen and macular degeneration maps to chromosome 6q14. Am J Ophthalmol.  130:197-202.

Stewart, S., Sundaram, M., Zhang, Y., Lee, J., Xiong, Y. Han, M., and Guan, K-L. (1999). Kinase Suppressor of Ras (KSR) forms a multi-protein signaling complex and modulates MEK localization. MCB, 19, 5523-5534.
Li, W., Han, M. and Guan, K.L. (2000).  The Leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf.  Gen & Dev.14, 895-900.

Fay, D.S. and Han, M. (2000). The Synthetic Multivulval Genes of C. elegans: Functional redundancy, Ras-antagonism, and cell fate determination. Genesis.  26, 279-284.

Grant, K, Hanna-Rose, W. and Han, M. (2000). Sem-4 promotes Caenorhabditis elegans vulval  fate determination through regulation of lin-39 hox. Devel. Biol.  224, 496-506.

Han, M. (2000). Studies on Ras-mediated signal transduction in C. elegans. In Sterm Cells and Development. Ed. By Jinseng Ye, Tian Xu, Tang Xifang and Bei
Haitial.  Medical Science Press. Beijing, China.

Chen, Z. and Han, M.(2000). Building a protein interaction map:research in the post-genomic era. BioEssays,22, 503-6.

Hanna-Rose, W. and Han, M. (2000). Getting your signal crossed. Curr. Opin. in Dev. Genetics. 10, 523-528.

Fay, D. S. and Han, M. (2000). Mutations in the C. elegans cyclin E gene reveal a timing mechanism that controls vulval cell differentiation. Development, 18,4049-4060.

2001

Zhang K, Kniazeva M, Han M, Li W, Yu Z, Yang Z, Li Y, Metzker ML, Allikmets R, Zack DJ, Kakuk, LE, Lagali PS, Wong PW, MacDonald IM, Sieving PA,
Figueroa DJ, Austin CP, Gould RJ, Ayyagari R, Petrukhin K.  (2001). A 5bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nature Genetics, 27, 89-93.

Yoder, J. and Han, M. (2001).  Cytoplasmic dynein light intermediate is required for discrete aspects of mitosis in Caenorhabditis elegans.  Mol. Cell. Biol  12, 2921-2933.

Chen, Z., Han, M. (2001)  Role of C. elegans lin-40 MTA in vulval fate specification and morphogenesis. Development. 128, 4911-4921.

Starr, D, Hermann, GJ., Malone, C. Fixsen, W., Priess, J. Horvitz, HR and Han, M. (2001). unc-83 encodes a novel component of the nuclear envelope and is essential for proper nuclear migration. Development.  128, 5039-5050.

Chen, Z. and Han, M. (2001). Role of Rb/E2F, the NuRD Complex, and Ras in Regulating a lin-39 Hox-mediated Cell Fusion Process during Vulval Fate Specification in C. elegans Curr. Biol. 11, 1874-1879.

Spencer, A., Orita, S., Malone, C., and Han, M. (2001) A RHO GTPase mediated pathway is required during P cell migration in C. elegans. Proc. Natl. Acd. Sci.  USA. 98, 13132-13137.


2002

Hanna-Rose, W. and Han, M. (2002). The Caenorhabditis elegans EGL-26 protein mediates vulval cell morphogenesis.  Devel. Bio. 24, 247-258. (Cover illustration)

Antoshechkin, I. and Han, M. (2002). Caenorhabditis elegans evl-20 gene encodes a functional homologue of human small GTPase ARL2 and regulates cytoskeleton dynamics during cytokinesis and morphogenesis. Developmental Cell, 2, 579-591.

Starr, D. and Han, M. Role of ANC-1 in Tethering Nuclei to the Actin Cytoskeleton. Science. 298, 406-409.

Suzuki, Y., Morris, G., Han, M. and Wood, W.B. (2002). A cuticle collagen encoded by the lon-3 gene may be a target of TGF-beta signaling in determining Caenorhabditis elegans body shape. Genetics, in press.

Fay, D., Keneen, S. and Han, M. (2002)  fzr-1 and lin-35/Rb Function Redundantly to Control Cell Proliferation in C. elegans as Revealed by
Nonbiased Synthetic Screen. Genes & Dev. 16. 503-517. (Cover illustration)


2003

Fay D., Large, E. Han, M. and Darland, M. (2003) lin-35/Rb and ubc-18, an E2 ubiquitin-conjugating enzyme, function redundantly to control
pharyngeal morphogenesis in C. elegans  Development.130, 3319-3330.

Kniazeva, M., Sieber, M. McCauley. S. Zhang, K. Watts, J., Han, M. (2003). Suppression of C. elegans ELO-2 function results in disruption of