hausman@bu.edu

Cell Signaling and Gene Regulation Cancer Biology Developmental Biology Cell and Molecular Biology

Professor of Biology
Ph.D., Northwestern University, 1971

Developmental biology, cell-cell interactions and gene expression

We are interested in the interactions of the proteins and carbohydrates that make up the adhesion-signaling complexes on the surface of cells in a multicellular organism.   Traditionally, these processes have been viewed as separate cell to cell and cell to matrix adhesions and cell to cell signaling processes usually involving transmembrane receptors.   However, progress over the past five years has demonstrated two important phenomena: first these are not simple systems but instead often complexes of dozens of different macromolecules which affect each other's activity, and second that the line between the two types of adhesion and the processes of signaling between cells has become blurred as the same molecules participate in several processes and often the same large complex carries out more than one function.   A good example of these phenomena are the finding that integrins -the primary family of cell-matrix adhesion molecules- undergo a dramatic change in conformation among 3-4 states of different ligand-binding ability and that this change is regulated by binding of cytosolic proteins to their C-termini, binding of different matrix ligands -and most relevant to our research- interactions between the partners within the integrin heterodimer and interactions with other cell surface-associated molecules.

The effective function of such interaction complexes is critical to establishment and maintenance of the differentiated state in multicellular organisms.   Isolated normal cells do not function well.   This is apparent in the simple system that we study, the re-aggregation in vitro of cells dispersed from the embryonic chick retina.   The retina is both an approachable tissue and a good model for the complex interactions of the central nervous system and the chick retina is both large and easily obtained.   After re-aggregation the cells will normally reassemble the tissue and continue to differentiate beyond that stage that they had previously attained.   However, if the interactions of the cells with each other -both adhesive and signaling- and with the matrix are blocked the cells will cease neuronal differentiation and, as we have recently observed, initiate programmed cell death.

Our probe into this model system is the retina cell recognition protein, cognin.   This is a product of the chicken protein disulfide isomerase (PDI) gene that is proteolytically processed in a tissue-limited manner which functions at the surface of the retinal cells to modify the conformation of selected proteins by isomerizing their disulfide bonds, presumably to accommodate necessary changes in conformation.   If cognin function is blocked in the tissue or the in vitro system, the tissue falls apart or the cells fail to aggregate and normal cell differentiation ceases.   Related protein disulfide isomerases function at the surfaces of a limited number of other cell types, to date platelets and lymphocytes.   Interestingly, in immune cells the PDI plays and important role in susceptibility to HIV infection. Whether these are all the same protein or other members of the thioreductase superfamily is not clear as recent investigations by us indicate that there are six proteins in chicken and seven in humans with the requisite motifs and activities.

Understanding the function of the PDIs in these and other systems, hence understanding the systems requires identifying the enzyme target, the substrate which is isomerized.   We are approaching this experimentally by a variety of methods and have identified likely targets by protein interaction cloning, protein cross-linking and the use of antibodies to predicted candidates.   Finally, we are currently preparing material for mass spectroscopy with subsequent interpretation of the complexities of the cross-linker.

Hausman, R.E. 2006. Ocular extracellular matrices. Progress in Retinal and Eye Research (invited review).   In press.

Mukherjee RS, Hausman RE. 2004. Cloning of chicken choline acetyltransferase and its expression in early embryonic retina. Brain Res Mol Brain Res. Oct 22;129(1-2):54-66.

Pariser HP, Zhang J, Hausman RE. 2000. The cell adhesion molecule retina cognin is a cell surface protein disulfide isomerase that uses disulfide exchange activity to modulate cell adhesion. Exp Cell Res. Jul 10;258(1):42-52.

Pariser, H.P., Rakeman, A., and Hausman, R.E. 1998. Thioreductase activity of retina cognin and its role in cell adhesion. Develop. Brain Res. 111, 1-9.

Hausman RE, Ren Y, Ruiz JF, Shah BH. 1998. Insulin-mediated stimulation of ChAT and c-Jun in the developing retina neurons involves PI 3-kinase. Biochem Soc Trans. Nov;26(4):S312 (short paper).

Holdengreber, V., Ren, Y., Ben-Shaul Y., and Hausman, R.E. 1998. Co-localization of the insulin receptor, jun protein and choline acetyltransferase in embryonic chick retina. Exptl. Eye Res. 66, 307-314.

Phillips, J.L., Holdengreber, V., Ben-Shaul, Y., Zhang, J., Tolan, D.R., and Hausman, R.E. 1997. Developmental localization of retina cognin synthesis by in situ hybridization. Develop. Brain Res. 104, 143-152.

Phillips, J.L., Tolan, D.R., and Hausman, R.E. 1997. Antisense inhibition of retina cognin expression modulates differentiation of retinal neurons in culture. Mol. Vision 3, 12

Phillips, J.L., Holdengreber, V., Ben-Shaul, Y., Zhang, J., Tolan, D.R., and Hausman, R.E. 1997. Developmental   localization of retina cognin synthesis by in situ hybridization. Develop. Brain Res. 104 , 143-152.

Questions and comments are always welcome.
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This document was last modified on December 12, 2006.