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Dr. Bem Culiat
Keywords:
Molecular Genetics, Functional Genomics, Mouse mutagenesis with N-ethyl-N-nitrosourea (ENU),
Annotation of human chromosomes 5, 16 and 19, skeletal development, craniofacial and spinal defects
Education
B.S. & M.S.: University of the Philippines
Ph.D.: University of Tennessee, ORNL Graduate School for Biomedical Sciences
Research Area:
Dr. Culiat's research is focused on using the mouse as a model to elucidate complex biological pathways.
The main approach is to generate and characterize mouse mutations in order to determine the whole organism
functions of mammalian genes and understand how perturbations in gene functions lead to birth defects and
diseases. The Culiat Lab is particularly interested in studying the underlying molecular mechanisms of
skeletal anomalies in the skull and vertebral column.
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Description of Research: |
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Insights into how alterations in genes and gene interactions controlling complex biological pathways cause
hereditary human birth defects and diseases can be obtained by analyzing mouse mutations. The ability to efficiently
generate and characterize the impact of mutant genes has progressed tremendously due to the rapid pace of developments
in: manipulation of the mouse genome, genome sequencing, robust high-throughput mutation scanning technologies,
genome-wide expression strategies (e.g. microarrays and qRTPCR), bioinformatics and computational biology. The
Culiat lab is employing these various techniques and resources in three projects:
Functional Annotation of Human Chromosomes 5, 16 and 19
Genes with Gene-Driven Mutagenesis in Mice.
In this large collaborative project at ORNL, we are generating ENU-induced mutations for genes that are predicted
to be important in a variety of biological pathways such as: immune response, behavior (learning, memory and drug
dependence), intracellular transport and trafficking of proteins, skeletal development and imprinting. We have
selected genes that contain highly conserved protein domains across distantly related genomes and then perform
high-throughput screening of a cryopreserved bank of 4000 DNAs, cDNAs and sperm from mice carrying mutations
induced by ENU. These mouse mutations are primarily single base pair substitutions that result in amino acid
changes in the corresponding protein. Since an estimated 60-70% of human disorders and differences in human
susceptibility are governed by point mutations or single nucleotide polymorphisms (SNPs), these ENU-induced
mutations are valuable animal models for investigating human gene functions.
Elucidating the role of the Nell1 gene in osteoblast and chrondrocyte differentiation
during skull and vertebral column development.
Nell1 is a protein kinase C beta 1-binding protein that is important in cell growth and
differentiation. Overexpression of Nell1 in both man and mouse induces craniosynostosis, the premature
fusion of cranial sutures in the skull before brain development is completed. Loss-of-function mutations in
Nell1 generated in our lab are homozygous lethal and mutant mouse fetuses exhibit alterations
in the size and shape of the skull, abnormal spine curvature and ribcage morphology. The loss of
Nell1 expression also leads to a significant reduction in the expression of genes coding for
extracellular matrix, cell adhesion and communication proteins that are essential in the differentiation
of osteoblasts and chondrocytes. We are determining the molecular and cellular mechanisms mediated by
Nell1
in the formation of bone and cartilage during fetal development.
Systems Biology of the Mammalian Cilium: A Cellular Organelle Essential for Human Health and Development.
A Systems Biology approach is being applied to understand cilia function in human health and disease.
Mouse mutations for genes that are predicted to be essential for the assembly and function of cilia (based on
proteomics and genomics data) are being generated and then phenotyped at the molecular, cellular and whole-animal
levels. This project is in collaboration with colleagues at ORNL (Drs. Ed Michaud and Mitch Klebig) and experts
in cilia structure and function at the University of Alabama at Birmingham.
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Recent Publications: |
- Desai, J., Shannon, M. E., Johnson, M. D., Ruff, D. W., Hughes, L. A., Kerley, M. K., Carpenter, D. A., Johnson, D. K.,
Rinchik, E. M. and Culiat, C. T. (2006)
Nell-1 deficient mice have reduced expression of extracellular matrix proteins
causing cranial and vertebral defects.
Human Molecular Genetics 15(8), 1329-1341.
- Sakharkar, K. R., Sakharkar, M. K., Culiat, C. T., Vincent, C. T. K. and Pervaiz, S. (2006)
Functional and evolutionary analyses on expressed intronless genes in the mouse genome.
FEBS Letters 580(5), 1472-1478.
- Michaud, E. J., Culiat, C. T., Klebig, M. L., Barker, G., Cain, K. T., Carpenter, D. J., Easter, L. L.,
Foster, C. M., Gardner, A. W., Geiger, J. , Guo, Z. Y., Houser, K. J., Hughes, L. A., Kerley, M. K., Liu, Z., Olszewski, R. E.,
Pinn, I., Shaw, G. D., Shinpock, S. G., Wymore, A. M., Rinchik, E. M. and Johnson, D. K. (2005)
Efficient gene-driven germ-line point mutagenesis of C57BL/6J mice.
BMC Genomics 6:164.
- Culiat, C.T., Klebig, M. L., Liu, Z., Monroe, H., Stanford, B., Desai, J., Tandan, S.,
Hughes, L., Kerley, M. K., Carpenter, D. A., Johnson, D. K., Rinchik, E. M., and Li, Q.
(2005) Identification of mutations from phenotype-driven ENU mutagenesis in mouse chromosome 7.
Mammalian Genome 15, 1-13.
- Elso, C., Lu, X., Culiat, C.T., Rutledge, J., Cacheiro, N., Generoso, W., and Stubbs, L.
(2004) Heightened susceptibility to gastric infection, chronic gastritis, and metaplasia in
Kcnq1 mutant mice.
Human Molecular Genetics 13, 2813-2821.
- Li, Q., Liu, Z., Monroe, H., and Culiat, C. T.
(2002) An Integrated Platform for Detection of DNA Sequence Variants Using Capillary
Array Electrophoresis. Electrophoresis, 23:1499-1511.
- Aponte, J.L., Sega, G.A., Hauser, L.J., Dhar, M.S., Withrow, C.M., Carpenter, D.A., Rinchik, E.M.,
Culiat, C.T. and Johnson, D.K.
Point mutations in the murine fumarylacetoacetate hydrolase gene:
Animal models for the human genetic disorder hereditary tyrosinemia type 1,
Proc. Natl. Acad Sci, USA, 98: 641-645, 2000.
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Selected Publications |
- Johnson, Dabney K., Carpenter, Donald A., Culiat, Cymbeline T.,
Goss, Karen A., Klebig, Mitchell L., Michaud, Edward J., Miller, Darla R., Russell, Liane B.,
You, Yun, and Rinchik, Eugene M.
A phenotype-driven approach to the molecular and functional analysis of the mouse genome.
Invited article for the Proceedings of the 1999 US/Japan meeting, National Research Council,
Washington DC, pp.105-115.
- Culiat, C. T., E. A. Carver, M. Walkowicz, E. M. Rinchik, N. L. A. Cacheiro, L. B. Russell,
W. M. Generoso and L. J. Stubbs. Induced mouse chromosomal rearrangements as tools for identifying
critical developmental genes and pathways. Reproductive Toxicology 11, 345-351, 1997.
- D. K., L. J. Stubbs, C. T. Culiat, C. S. Montgomery,
L. B. Russell, and E. M. Rinchik. Molecular analysis of 36 mutations
at the mouse pink-eyed dilution (p) locus. Genetics,
141: 1563-1571, 1995.
- Culiat, C. T., L. Stubbs, R. P. Woychik, L. B. Russell, D. K. Johnson and
E. M. Rinchik.
Deficiency of the beta3 subunit of the type-A gamma-aminobutyric acid receptor
causes cleft palate in mouse. Nature Genetics 11: 344-346, 1995.
(Publication of Ph.D Thesis)
- Culiat, C. T., Stubbs, L., Montgomery, C., Russell, L. B., and Rinchik, E. M. (1994)
Phenotypic consequences of the deletion of the gamma3, alpha5 or beta3 subunit of the
type-A-gamma-aminobutyric acid receptor in mice
Proc. Natl. Acad. Sci. USA, 91:2815-2818.
- Culiat, C. T., Stubbs, L., Nicholls, R. D., Montgomery, C. S., Russell, L. B.,
Johnson, D. K. and Rinchik, E. M. (1993)
Concordance between isolated cleft palate in mice and alterations within a region including the
gene encoding the beta 3 subunit of the type-A gamma- aminobutyric acid receptor.
Proc. Natl. Acad. Sci. USA 90:5105-5109.
- Sega, G. A., Valdivia Alcota, R. P., Tancongco, C. P. and Brimer, P. A. (1989)
Acrylamide Binding to the DNA and protamine of spermiogenic stages in the mouse and its relationship to genetic damage.
Mutation Res. 216, 221-230.
- Duka I. M., Tancongco, C. P., Demayo, C. G., Sta. Iglesia, D. D., and Rimando, L.
(1988) Biology 1 Laboratory Manual: An Investigative Approach.
University of the Philippines Press, Laguna, Philippines.
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Selected Abstracts |
- Desai, J., L. Hughes, J. Millsaps, M. Kerley, D. Carpenter, E. Rinchik, M. Johnson and C. T. Culiat.
Characterization of Mouse Nell1: A gene coding for a novel PKC-binding Protein.
Women in Science Meeting. May 1, 2006. Oak Ridge National Laboratory. Oak Ridge, TN.
- Michaud, E. J., C. T. Culiat, M. L. Klebig, G. Barker, K. T. Cain, D. J. Carpenter,
L. L. Easter, C. M. Foster, A. W. Gardner, J. Geiger, Z. Y. Guo, K. J. Houser, L. A. Hughes, M. K. Kerley,
Z. Liu, R. E. Olszewski, I. Pinn, G. D. Shaw, S. G. Shinpock, A. M. Wymore, E. M. Rinchik, and D. K. Johnson.
(2004) Functional Annotation of Human Genes by Gene-Driven ENU Mutagenesis in Mice.
18th Annual International Mouse Genome Conference, Seattle, Washington.
- Rinchik, E. M., D. K. Johnson, D. Miller, C. T. Culiat and E. J. Michaud
(2003) Chemical mutagenesis of the mouse germline: new models for genetic diseases and for dissecting
basic biological processes. FASEB Journal 17(5):A1168, Part 2, Suppl.
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Invited Talks |
- Mouse Mutagenesis and Systems Biology at ORNL. Michaud, E. J. and C. T. Culiat. Mouse Mutagenesis Workshop.
Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Sept 15-17, 2005.
- Using the Mouse to Model Human Birth Defects in the Skull and Spine.
SULI Oak Ridge Science Semester. April 20, 2005. ORISE-Oak Ridge National Laboratory.
- Gene-Driven Mouse Mutagenesis Using the ORNL Cryopreserved Mutant Mouse Bank. Culiat, C. T.,
E. J. Michaud, D. K. Johnson and E. M. Rinchik.
4th Annual Retreat of the Tennessee Mouse Genome Consortium. December 5, 2003. Vanderbilt University, TN.
- Functional Annotation of Human Genome Sequence Using Mutant Mouse Models:
Harnessing Bioinformatics and High-throughput Mutation Scanning. May 1, 2002.
Duke University Medical Center, Durham, NC.
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Contact Information for Dr. Cymbeline T. Culiat |
Senior Research Staff Scientist
Oak Ridge National Laboratory
Mammalian Genetics & Genomics
Biosciences Division
Oak Ridge, TN 37831-6445
Telephone: (865) 241-0672
Fax: (865) 574-5345
E-mail: culiatct@ornl.gov
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