The objective of our research is to better understand how specific patterns of gene expression cause the right kinds of neurons to be generated in different regions of the central nervous system. Our efforts are currently focussed on the mammalian hindbrain, a particularly informative model system. During development the hindbrain is briefly organized into a series of repeating units, called rhombomeres, that transiently expresses different sets of genes. The differences in gene expression among rhombomeres are thought to give rise to the different patterns of neuron differentiation that in each rhombomere. These patterns of gene expression can also influence the development of craniofacial tissues, for some rhombomeres generate the neural crest cells that form skeletal and connective tissues of the head and neck.

Establishing correlations between early gene expression and later differentiation is made difficult by the cellular proliferation and migration that occurs between gene expression and overt differentiation. It is often impossible to tell which cells in mature tissues arise from ancestors that expressed a particular gene, and which did not. To address this problem we devised a means of heritably marking the lineages generated by progenitors that express specific genes. We use homologous recombination in mouse embryonic stem cells to replace the normal coding sequence of a gene with the coding sequence for a site-specific recombinase. We then generate mice that contain both this altered allele and a marker gene whose expression is dependent on recombination by the site-specific recombinase. Recombinase expression in the progenitors that normally express the gene of interest leads to the activation of the marker gene in those cells, and in all of their progeny throughout development, even if the latter no longer express the gene of interest.

To date, we have used this approach to determine the fates of cells in rhombomere 4 that express a member of the HOX gene family, hoxb-1, at high levels. Quite unexpectedly, we found that some descendants of rhombomere 4 migrate substantial distances within the central nervous system to form discrete neuronal populations that are separated from the principal descendant cohort, and we established that these migrations were dependent on the normal function of the hoxb-1 locus. We also determined the fates of neural crest cells that form the connective and skeletal tissues of the second branchial arch. Among other findings, we made the surprising observation that one ossicle of the middle ear, the malleus, was comprised of both first and second arch components. In the immediate future we will use analogous strategies to determine the fates of cells from other rhombomeres and the dependence of these fates on specific patterns of gene expression.

1. O’Gorman S. (2005)
   Second branchial arch lineages of the middle ear of wild-type and Hoxa2 mutant mice. Dev Dyn. 2005 Sep; 234(1):124-131.
   
2. Sans N, Vissel B, Petralia RS, Wang YX, Chang K, Royle GA, Wang CY, O’Gorman S, Heinemann SF, Wenthold RJ. (2003)
   Aberrant formation of glutamate receptor complexes in hippocampal neurons of mice lacking the GluR2 AMPA receptor subunit. J Neurosci. 2003 Oct 15; 23(28):9367-9373.
   
3. Selleri L, Depew MJ, Jacobs Y, Chanda SK, Tsang KY, Cheah KS, Rubenstein JL, O’Gorman S, Cleary ML. (2001)
   Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. Development. 2001 Sep; 128(18):3543-3557.
   
4. DiMartino JF, Selleri L, Traver D, Firpo MT, Rhee J, Warnke R, O’Gorman S, Weissman IL, Cleary ML. (2001)
   The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver. Blood. 2001 Aug 1; 98(3):618-626.
   
5. Vissel B, Royle GA, Christie BR, Schiffer HH, Ghetti A, Tritto T, Perez-Otano I, Radcliffe RA, Seamans J, Sejnowski T, Wehner JM, Collins AC, O’Gorman S, Heinemann SF. (2001)
   The role of RNA editing of kainate receptors in synaptic plasticity and seizures. Neuron. 2001 Jan; 29(1):217-227.
   
6. Jimenez GS, Nister M, Stommel JM, Beeche M, Barcarse EA, Zhang XQ, O’Gorman S, Wahl GM. (2000)
   A transactivation-deficient mouse model provides insights into Trp53 regulation and function. Nat Genet. 2000 Sep; 26(1):37-43.
   
7. Blume-Jensen P, Jiang G, Hyman R, Lee KF, O’Gorman S, Hunter T. (2000)
   Kit/stem cell factor receptor-induced activation of phosphatidylinositol 3’-kinase is essential for male fertility. Nat Genet. 2000 Feb; 24(2):157-162.
   
8. Sailer A, Swanson GT, Perez-Otano I, O’Leary L, Malkmus SA, Dyck RH, Dickinson-Anson H, Schiffer HH, Maron C, Yaksh TL, Gage FH, O’Gorman S, Heinemann SF. (1999)
   Generation and analysis of GluR5(Q636R) kainate receptor mutant mice. J Neurosci. 1999 Oct 15; 19(20):8757-8764.
   
9. Zeh K, Andahazy M, O’Gorman S, Baribault H. (1998)
   Selection of primary cell cultures with cre recombinase induced somatic mutations from transgenic mice. Nucleic Acids Res. 1998 Sep 15; 26(18):4301-4303.
   
10. O’Gorman S, Dagenais NA, Qian M, Marchuk Y. (1997)
    Protamine-Cre recombinase transgenes efficiently recombine target sequences in the male germ line of mice, but not in embryonic stem cells. Proc Natl Acad Sci U S A. 1997 Dec 23; 94(26):14602-14607.
    
11. O’Gorman S, Wahl GM. (1997)
    Mouse engineering. Science. 1997 Aug 22; 277(5329):1025.
    
12. Aladjem MI, Brody LL, O’Gorman S, Wahl GM. (1997)
    Positive selection of FLP-mediated unequal sister chromatid exchange products in mammalian cells. Mol Cell Biol. 1997 Feb; 17(2):857-861.
    
13. O’Gorman S, Fox DT, Wahl GM. (1991)
    Recombinase-mediated gene activation and site-specific integration in mammalian cells. Science. 1991 Mar 15; 251(4999):1351-1355.
    
14. Windle B, Draper BW, Yin YX, O’Gorman S, Wahl GM. (1991)
    A central role for chromosome breakage in gene amplification, deletion formation, and amplicon integration. Genes Dev. 1991 Feb; 5(2):160-174.
    
15. White WF, O’Gorman S, Roe AW. (1990)
    Three-dimensional autoradiographic localization of quench-corrected glycine receptor specific activity in the mouse brain using 3H-strychnine as the ligand. J Neurosci. 1990 Mar; 10(3):795-813.