The National Institute of Diabetes & Digestive & Kidney Diseases

We are interested in genes that regulate the choice of cell fate (eg. nerve, muscle, skin) during development. Our model system is the nematode C. elegans, a small free-living worm that is widely used for developmental studies because of its small size, ease of culture, simple anatomy, rapid proliferation, and genetic manipulability. Much of our work is focused on muscle development, although we are not limited to myogenesis alone.

Our approach to understanding C. elegans myogenesis has been to identify candidate genes involved in the process and study their function by reducing or eliminating gene activity through mutation or RNA-mediated interference (RNAi). These mutational studies are carried out in the whole organism and the phenotypic effects are determined at the single cell level, providing organismal context for gene function.

We have defined in C. elegans the function of several transcription factors related to the vertebrate myogenic regulators MyoD, E, Twist, SRF and Mef-2. Our work has clarified the specific developmental roles of these factors and added new insights into myogenesis by demonstrating that 1) there is a MyoD-independent pathway for striated muscle formation, 2) MyoD is required for development of a non-muscle cell fate, 3) Twist regulates pattern, not cell fate or proliferation, 4) there are distinct transcriptional mechanisms regulating myogenesis in embryogenesis versus post-embryonic development, 5) the early C. elegans embryo developmental program is remarkably flexible, and 6) animal muscle types appear to have evolved from a common ancient contractile cell type.

We have recently developed an in vivo system of converting most somatic blastomeres into a single cell type by over-expressing certain "master" transcription factors. This has allowed us to follow the development of these different tissues in the embryo in the absence of other cell types. Using whole genome microarray analysis, we have begun to profile gene expression during the time course of early development. This analysis has identified candidate regulatory transcription factors that we are currently characterizing by mutation, RNAi knock-down, and over-expression in transgenic animals.

In addition to our interests in muscle development, there are several other projects in the lab. These include a bioinformatic approach to identify cis-acting promoter sequences regulating gene expression, the study of nuclear hormone receptor genes and development (collaboration with Dr. Marta Kostrouchova), and the role of a sugar-sensing pathway in development and disease (collaboration with Dr. John Hanover).

1. Forsythe ME, Love DC, Lazarus BD, Kim EJ, Prinz WA, Ashwell G, Krause MW, Hanover JA Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer. Proc Natl Acad Sci U S A (103): 11952-7, 2006. [Full Text/Abstract]

2. Fukushige T, Brodigan TM, Schriefer LA, Waterston RH, Krause M Defining the transcriptional redundancy of early bodywall muscle development in C. elegans: evidence for a unified theory of animal muscle development. Genes Dev , 2006. [Full Text/Abstract]

3. Hanover JA, Forsythe ME, Hennessey PT, Brodigan TM, Love DC, Ashwell G, Krause M A Caenorhabditis elegans model of insulin resistance: Altered macronutrient storage and dauer formation in an OGT-1 knockout. Proc Natl Acad Sci U S A (102): 11266-71, 2005. [Full Text/Abstract]

4. Fukushige T, Krause M The myogenic potency of HLH-1 reveals wide-spread developmental plasticity in early C. elegans embryos. Development (132): 1795-805, 2005. [Full Text/Abstract]

5. Cai T Fukushige T Notkins AL Krause M Insulinoma-Associated Protein IA-2, a Vesicle Transmembrane Protein, Genetically Interacts with UNC-31/CAPS and Affects Neurosecretion in Caenorhabditis elegans. J Neurosci (24): 3115-24, 2004. [Full Text/Abstract]

6. Brodigan TM Liu J Park M Kipreos ET Krause M Cyclin E expression during development in Caenorhabditis elegans. Dev Biol (254): 102-15, 2003. [Full Text/Abstract]

7. Corsi AK Brodigan TM Jorgensen EM Krause M Characterization of a dominant negative C. elegans Twist mutant protein with implications for human Saethre-Chotzen syndrome. Development (129): 2761-72, 2002. [Full Text/Abstract]

8. Tonkin LA Saccomanno L Morse DP Brodigan T Krause M Bass BL RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans. EMBO J (21): 6025-35, 2002. [Full Text/Abstract]

9. Kostrouchova M Krause M Kostrouch Z Rall JE Nuclear hormone receptor CHR3 is a critical regulator of all four larval molts of the nematode Caenorhabditis elegans. Proc Natl Acad Sci U S A (98): 7360-5, 2001. [Full Text/Abstract]

10. Corsi AK Kostas SA Fire A Krause M Caenorhabditis elegans twist plays an essential role in non-striated muscle development. Development (127): 2041-51, 2000. [Full Text/Abstract]

11. Dichoso D Brodigan T Chwoe KY Lee JS Llacer R Park M Corsi AK Kostas SA Fire A Ahnn J Krause M The MADS-Box factor CeMEF2 is not essential for Caenorhabditis elegans myogenesis and development. Dev Biol (223): 431-40, 2000. [Full Text/Abstract]

12. Zhang JM Chen L Krause M Fire A Paterson BM Evolutionary conservation of MyoD function and differential utilization of E proteins. Dev Biol (208): 465-72, 1999. [Full Text/Abstract]

13. Park M Krause MW Regulation of postembryonic G(1) cell cycle progression in Caenorhabditis elegans by a cyclin D/CDK-like complex. Development (126): 4849-60, 1999. [Full Text/Abstract]

14. Harfe BD Vaz Gomes A Kenyon C Liu J Krause M Fire A Analysis of a Caenorhabditis elegans Twist homolog identifies conserved and divergent aspects of mesodermal patterning. Genes Dev (12): 2623-35, 1998. [Full Text/Abstract]

15. Kostrouchova M Krause M Kostrouch Z Rall JE CHR3: a Caenorhabditis elegans orphan nuclear hormone receptor required for proper epidermal development and molting. Development (125): 1617-26, 1998. [Full Text/Abstract]

16. Harfe BD Branda CS Krause M Stern MJ Fire A MyoD and the specification of muscle and non-muscle fates during postembryonic development of the C. elegans mesoderm. Development (125): 2479-88, 1998. [Full Text/Abstract]

17. Krause M Park M Zhang JM Yuan J Harfe B Xu SQ Greenwald I Cole M Paterson B Fire A A C. elegans E/Daughterless bHLH protein marks neuronal but not striated muscle development. Development (124): 2179-89, 1997. [Full Text/Abstract]

18. Lubas WA Frank DW Krause M Hanover JA O-Linked GlcNAc transferase is a conserved nucleocytoplasmic protein containing tetratricopeptide repeats. J Biol Chem (272): 9316-24, 1997. [Full Text/Abstract]

19. Krause M MyoD and myogenesis in C. elegans. Bioessays (17): 219-28, 1995. [Full Text/Abstract]

20. Krause M Harrison SW Xu SQ Chen L Fire A Elements regulating cell- and stage-specific expression of the C. elegans MyoD family homolog hlh-1. Dev Biol (166): 133-48, 1994. [Full Text/Abstract]

21. Chen L Krause M Sepanski M Fire A The Caenorhabditis elegans MYOD homologue HLH-1 is essential for proper muscle function and complete morphogenesis. Development (120): 1631-41, 1994. [Full Text/Abstract]

22. Chen L Krause M Draper B Weintraub H Fire A Body-wall muscle formation in Caenorhabditis elegans embryos that lack the MyoD homolog hlh-1. Science (256): 240-3, 1992. [Full Text/Abstract]

23. Mello CC Draper BW Krause M Weintraub H Priess JR The pie-1 and mex-1 genes and maternal control of blastomere identity in early C. elegans embryos. Cell (70): 163-76, 1992. [Full Text/Abstract]

24. Krause M Fire A Harrison SW Priess J Weintraub H CeMyoD accumulation defines the body wall muscle cell fate during C. elegans embryogenesis. Cell (63): 907-19, 1990. [Full Text/Abstract]

25. Krause M Fire A Harrison SW Priess J Weintraub H CeMyoD accumulation defines the body wall muscle cell fate during C. elegans embryogenesis. Cell (63): 907-19, 1990. [Full Text/Abstract]

26. Krause M Hirsh D A trans-spliced leader sequence on actin mRNA in C. elegans. Cell (49): 753-61, 1987. [Full Text/Abstract]