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Mammalian developmental genetics and models of human disease
Genetic manipulations in the mouse are extremely powerful. Inbred strains of mice provide defined backgrounds
to study complex genetic interactions. Transgenesis to produce mutations that over-express or eliminate the function of genes
has established the mouse as a model organism for studying mammalian gene functions. Recently, forward genetics using chemical
mutagenesis has made the mouse a powerful organism to define gene functions and model human diseases on a large scale. Our lab
exploits each of these genetic techniques in a variety of projects designed to dissect the molecular genetic basis for hematopoiesis.
Hematopoiesis is a complex process that involves progressive differentiation steps towards lineage commitment from a
self-renewing stem cell. In mammals, differentiation of hematopoietic cells takes place in multiple sites and times during
development: the fetal yolk sac and mesodermal aortic/gonadal region, the fetal liver, and the bone marrow.
Insertional mutations caused by retroviruses in somatic cells often lead to leukemias or lymphomas, and allow the
molecular tagging of novel proto-oncogenes altered by the insertion. Studies of the role of the proto-oncogene in normal
cells leads to an understanding of how the altered gene causes the development of leukemia. We have established an extensive
viable mouse tumor bank from recombinant inbred AKXD mice, and have used genomic techniques to identify genomic sequences
flanking all of the retroviral insertions in the AKXD B-cell tumors. The genetic profile of insertion sites identifies
pathways that lead to the development of B-cell leukemia, while they define important events in B-cell differentiation.
The controlled genetic background of these strains allows for a genetic dissection of cancer susceptibility. Sequences
derived from the mouse are used to molecularly clone and localize the human homolog of the proto-oncogene. Often, these
studies show that the gene is involved in human cancer.
The chemical N-ethyl-N-nitrosourea (ENU) is a powerful mouse mutagen for forward genetic phenotype-
driven screens. Large-scale screens for developmental phenotypes must take into account the ease of recovering and
maintaining mutations that are detrimental to the organism. Chromosome engineering techniques can be used to design balancer
chromosomes that suppress recombination and are marked with a dominant coat color, which are ideal to isolate and maintain
detrimental mutations. We are using balancer chromosomes in ENU mutagenesis screens designed to define gene functions. The
phenotypes are relevant to human disease, causing cardiovascular, skeletal, hematopoietic, neurological, urogenital,
skin/coat, and metabolic defects. My lab focuses on mutations with defects in vasculogenesis or hematopoiesis. Other
mutations are supplied to the biomedical community. Our ultimate goal is to establish mouse models of human disease, and to
understand pathways of gene function during development.
Selected Publications
Perou CM, Moore KJ, Nagle DL, Misumi DJ, Woolf EA, McGrail SH, Holmgren L, Brody TH,
Dussault BJ Jr, Monroe CA, Duyk GM, Pryor RJ, Li L, Justice MJ, Kaplan J (1996) Identification
of the murine beige gene by YAC complementation and positional cloning. Nature Genetics
13:303-308.
Hansen GM, Justice MJ (1999) Activation of Hex and mEg5 by retroviral insertion
may contribute to mouse B-cell leukemia. Oncogene 18:6531-6539.
Hansen GM, Skapura D, Justice MJ (2000) Genetic profile of insertion mutations in mouse leukemias
and lymphomas. Genome Research 10:237-243.
Justice MJ (2000) Capitalizing on large-scale mouse mutagenesis screens. Nature Reviews
Genetics 1:109-115.
Headon DJ, Emmal SA, Ferguson BM, Tucker AS, Justice MJ, Sharpe PT, Zonana J, Overbeek PA (2001)
Gene defect in ectodermal dysplasia implicates a death domain adapter in development. Nature
414:913-916.
Hentges KE, Yarlagadda SP, Justice MJ (2002) Tnfrsf13c (Baffr) is mis-expressed in tumors
with murine leukemia virus insertions at Lvis22. Genomics 80:204-212.
Noveroske JK, Lai L, Gaussin V, Northrop JL, Nakamura H, Hirschi KK, Justice MJ (2002) Quaking
is essential for blood vessel development. Genesis 32:218-230.
Kile BT, Hentges KE, Clark AT, Nakamura H, Salinger AP, Liu B, Box N, Stockton DW, Johnson RL,
Behringer RR, Bradley A, Justice MJ (2003) Functional genetic analysis of mouse chromosome 11.
Nature 425:81-86.
George A, Morse HC 3rd, Justice MJ (2003) The homeobox gene Hex induces T-cell-derived
lymphomas when overexpressed in hematopoietic precursor cells. Oncogene 22:6764-6773.
Contact Information
- Monica J. Justice, Ph.D.
- Department of Molecular and Human Genetics
- Baylor College of Medicine
- One Baylor Plaza 410A
- Houston, Texas 77030, U.S.A.
- Lab Website
- Tel: (713) 798-5440
- Fax: (713) 798-5386
- E-mail: mjustice@bcm.tmc.edu
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