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James W. MahaffeyAssociate Professor of Genetics
PhD, The Johns Hopkins University, 1984 |
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Animal development---specification of body patternMy lab studies the genetic control of body pattern specification during animal embryogenesis. During the past decade, a major goal of developmental geneticists has been to determine how genes specify body pattern, but to date our understanding is still quite limited. A conserved group of genes encoding homeodomain class transcription factors (the HOM-C or hox genes) is responsible for establishing the anterior-posterior body pattern of all animals studied. These genes were initially identified by mutations causing homeotic transformations in the fruit fly, Drosophila melanogaster, but it is now known that related genes perform similar functions in all animals. The encoded proteins specify regional identity by selectively activating the necessary battery of "target" genes required to establish later cell fates. These include cell signaling molecules, other transcription factors, cytoskeletal components and molecules responsible for processes such as cell and tissue migration and cell death. Though
the HOM-C/hox genes encode transcription factors, we do not understand
how these factors coordinate the spatial and temporal aspects of target
gene expression in different tissues.
The main problem is that the encoded proteins all bind to a very
simple nucleotide sequence, so it is not clear how the HOM-C protein encoded
by the Deformed gene specifies head development while the protein encoded
by the Antennapedia gene specifies
trunk identity. My lab is using morphogenesis of the Drosophila
larval head as a model to understand HOM-C gene function. Recently,
we have identified a pair of neighboring genes encoding zinc finger transcription
factors, which appear to be involved with the HOM-C genes specifying head
development. These genes are partially
redundant during this aspect of pattern formation (though they may have
other independent roles later in development).
We have used the technique of RNA interference, in conjunction
with mutational analysis, to demonstrate that either of these genes is
sufficient for development of the embryonic head.
In the absence of both functions, head development is disrupted
in a manner similar to that observed when the head HOM-C genes are absent
(Deformed and Sex combs reduced).
Furthermore, expression of several Deformed target genes is disrupted
when the zinc finger proteins are absent. We predict that these zinc finger
genes encode cofactors that are necessary for target gene activation.
Perhaps an interaction between the zinc finger proteins and the
homeodomain-containing HOM-C proteins can supply the additional specificity
in DNA binding necessary for selection of the proper target genes needed
for segment-specific development. We are currently performing tests of
this hypothesis. Recent Publications:Robertson, L.K., and Mahaffey, J.W. 2004. Insect HOM-C genes and development-Lessons from Drosophila and beyond. In Comprehensive Insect Physiology, Biochemistry, Pharmacology, and Molecular Biology-Reproduction and Development (eds., L.I. Gilbert, K. Iatrou, and S. Gill) Elsevier Limited, London, UK. Robertson, L.K., Bowling, D.B., Mahaffey, J.P., Imiolczyk, B. and Mahaffey, J.W. 2004. An interactive network of zinc-finger proteins, contributes to regionalization of the Drosophila embryo and establishes domains of HOM-C protein function. Development 131: 2781-2789. Robertson, L.K., Dey, B.K., Campos, A.R. and Mahaffey, J.W. 2002. Expression of the Drosophila gene disconnected using the UAS/GAL4 system. Genesis 34:103-106. Mahaffey, J.W., Griswold, C.M. and Cao, Q.-M. 2001.
The Drosophila genes disconnected
and disco-related are redundant
with respect to larval head development and accumulation of mRNAs from
Deformed target genes. Genetics. 157, 225-236. Pederson, J.A., LaFollette, J.W., Gross, C., Veraksa, A., McGinnis, W. and Mahaffey, J.W. 2000. Regulation by homeoproteins: a comparison of Deformed-responsive elements. Genetics 156, 677-686. [Abstract] Brown, S.P., Mahaffey, J.P., Lorenzen, M., Denell, R. and Mahaffey, J. 1999. Using RNAi to investigate orthologous homeotic gene function during development of distantly related insects. Evol. Dev. 1, 11-15. [Abstract] Fyrberg C., Becker J., Barthmaier P., Mahaffey J. and Fyrberg E. 1998. A family of Drosophila genes encoding quaking-related maxi-KH domains. Biochem. Genet. 36, 51-64. [Abstract] Fyrberg, C., Becker, J., Barthmaier, P., Mahaffey, J. and Fyrberg, E. 1997. Muscle-specific protein having RNA binding and signal transduction motifs. Gene 197, 315-323. [Abstract] Pederson, J. D., Kiehart, D. P. and Mahaffey, J. W. 1996. The role of HOM-C genes in segmental transformations: reexamination of the Drosophila Sex combs reduced embryonic phenotype. Developmental Biology 180, 131-142. [Abstract] Mohler, J., Mahaffey, J. W., Deutsch, E. and Vani, K. 1995. Control of Drosophila head segment identity by the bZIP homeotic gene cnc. Development 121, 237-247. [Abstract] Mahaffey, J.W., Jones, D.F., Hickel, J.A. and Griswold, C.M. 1993. Identification and characterization of a gene activated by the Deformed homeoprotein. Development 118, 203-214. [Abstract] For more information contact:
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