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Genetic and molecular mechanisms
of Hox patterning in mammalian development.
Hox genes are an evolutionarily conserved set of genes that are key regulators of anterior-posterior (AP) patterning during embryonic development. In mammals, 39 Hox genes are located in four clusters and each cluster is expressed collinearly such that 3’ genes are expressed the earliest and in the most anterior regions of the developing embryo, with increasingly 5’ genes being expressed slightly later and with more posterior expression limits during AP patterning. These 39 Hox genes are further subdivided into 13 paralogous groups and members within each of these groups have retained considerable functional redundancy throughout vertebrate evolution. My laboratory is interested in understanding the function of paralogous Hox genes in vertebrate development. We have engineered mutations in these genes in mice and are using these genetic tools to understand the function of these genes in vivo. Using a combination of mouse developmental genetics, molecular biology and biochemical approaches, we are dissecting the molecular mechanisms of Hox function during early embryonic patterning.
Our current research is focused mainly on three developmental systems: the kidney, the axial skeleton and the prostate. Using the kidney as a model organ system, we are characterizing the roles of the Hox10 and Hox11 paralogous genes in patterning the nephrogenic mesenchyme. Our results are demonstrating that the Hox11 paralogs interact with the conserved Pax-Eya-Six pathway during metanephric induction. Preliminary studies indicate that interaction between Hox genes and this regulatory network may be conserved in the development of other organ systems. These hypotheses are being tested at the biochemical, molecular and genetic levels.
Probably the most conserved and well-known function of Hox genes is in establishing the AP axis of the body plan. In vertebrates, this is born out in the patterning of the axial skeleton. We are continuing genetic studies with many paralogous mutants and establishing the genetic roles of each paralogous group in patterning the skeleton. We are also engineering new alleles in mice that allow real-time visualization of Hox protein expression in order to begin to dissect the important role Hox genes play in establishing the morphology of the vertebrate skeleton.
Recently, work in the lab has established that the Hox10 and Hox11 paralogous genes also play a critical role in the development and patterning of the prostate. Interestingly, different paralogous groups demonstrate regional differences in patterning the distinct lobes of this organ. As these Hox paralogous groups have been shown to highly up-regulated in prostate cancer, defining the function of these genes during prostate organogenesis will have implications not only for developmental biology, but potentially in understanding prostate cancer etiology as well.
- McIntyre, D.C., Rakshit, S, Yallowitz, A. R. Loken. L., Jeannotte, L, Capecchi, M.R., and Wellik, D.M. (2007), “Hox Patterning of the Vertebrate Rib Cage”, Development 134:2981-2989.
**highlighted in In This Issue and on the cover.
- Wellik, D.M., (2007) “Hox Patterning of the Vertebrate Axial Skeleton”, Developmental Dynamics 236:2454-2463.
- Gong, K-Q., Yallowitz, A.R., Sun, H.S., Dressler, G.R., Wellik, D.M., (2007). “A Hox-Eya-Pax Complex Regulates Kidney Developmental Gene Expression”, Molecular & Cellular Biology, in press.
- Wellik, D.M., and Capecchi, M.R. (2003). Paralogous Hox Genes Are Used for Global Patterning of the Mammalian Body Plan. Science, 301:363-367.
- Wellik, D.M., Hawkes, P.J. and Capecchi, M.R. (2002). Hox11 paralogous genes are essential for metanephric kidney induction. Genes & Development 16:1423-1432.
- Jia,X., Sicinski, R.R., Wellik, D.M., Taadikonda, P., Schnoes, H.K. and DeLuca, H.F. (1998). Identification of a new all-trans-retinol metabolite produced through a new retinol metabolic pathway. Biochemistry 37:5974-5980.
- Wellik, D.M., Norbach, D.H. and DeLuca, H.F. (1997). Retinol is specifically required during mid-gestation for neonatal survival. Am. J. Physiol. 272:E25-E29.
- Wellik, D.M. and DeLuca, H.F. (1996). Metabolites of all-trans retinol in day 10 conceptuses of vitamin A-deficient rats. Arch. Biochem. Biophys. 330(2):355-362.
- Wellik, D.M. and DeLuca, H.F. (1995). Retinol in addition to retinoic acid is required for successful gestation in vitamin A-deficient rats. Biol. Reprod. 53:1392-1397.
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