Past Research Programs

This page lists past research programs and those that are not under focused investigation.

  1. The Wnt/beta-catenin pathway in development and tumorigenesis
  2. The role of connexins in epithelial physiology
  3. Development of the bat mammary gland
  4. Id2 in epithelial physiology

The role of beta-catenin in signal transduction, cell fate determination and trans-differentiation

The Wnt/beta-catenin pathway has been the subject of recent interest with respect to signal transduction during cell fate determination and neoplastic transformation of mamamry epithelium (1). Wnt signalling through its receptor frizzled has been shown to phosphorylate disheveled (dsh), which in turn inhibits GSK3b function (Figure 1). Loss of GSK3b results in the stabilization and nuclear accumulation of b-catenin, which activates developmental programs in conjunction with LEF/TCF transcription factors. GSK3b normally phosphorylates Serine and Threonine residues in the N-terminal region of beta-catenin, which results in an APC-mediated ubiquitination and degration.

Our laboratory has explored the beta-catenin through the stabilization and thus activation of endogenous beta-catenin (1). This was accomplished through the deletion of exon 3 (which encodes amino acids 5-80) using Cre-loxP recombination (1, 2).

We were able to demonstrate a role for beta-catenin in signal transduction in mamamry epithelium. Specifically, we revealed that the activation of beta-catenin results in the loss of differentiation and the transdifferentiation of mammary epithelial cells into epidermis-like structures.

Current investigators:
Past LGP Investigators: Keiko Miyoshi, Brian Bierie, Fabienne LeProvost, Rashmi Nemade, Masa Nozawa, Chip Renou, Traudl Robinson, Jonathan Shillingford
Past Collaborators: Mark Taketo, Khash Khazaie

References

References

1. Renou, J.-P., Bierie, B., Miyoshi, K., Cui, Y., Djiane, J., Reichenstein, M., Shani, M. and Hennighausen, L. (2003) Identification of genes differentially expressed in mouse mammary epithelium transformed by an activated -catenin. Oncogene, 29, 4594-4610.

2. Biere, B., Nozawa, M., Renou, J.-P., Morgan, F., Oka, T., Taketo, M.M., Miyoshi, K. and Hennighausen, L. (2003) Beta-catenin induces neoplasia and transdifferentiation of mouse prostate epithelium. Oncogene, 22, 3875-3887.

3. Miyoshi, K., Rosner, A., Nozawa, M., Byrd, C., Morgan, F., Seldin, D.C., Schmidt, E.V., Taketo, M.M., Robinson, G.W., Cardiff, R.D. and Hennighausen, L. (2002) Activation of different wnt/ -catenin signaling components in mammary epithelium induces transdifferentiation and the formation of pilar tumors. Oncogene, 21, 5548-5556.

4. Miyoshi, K., Shillingford, J.M., LeProvost, F., Gounari, F., Bronson, R., von Boehmer, H., Taketo, M.M., Cardiff, R.D., Hennighausen, L. and Khazaie, K. (2002) Activation of beta-catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias. Proc. Natl. Acad. Sci. U.S.A., 99, 219-224.

5. Wagner, K.-U., Wall, R.J., St-Onge, L., Gruss, P., Garrett, L., Wynshaw-Boris, A., Li, M., Furth, P.A. and Hennighausen, L. (1997) Cre mediated gene deletion in the mammary gland. Nucleic Acids. Res. 25, 4323-4330.

6. Wagner, K.U., McAllister, K., Ward, T., Davis, B., Wiseman, R. and Hennighausen, L. (2001) Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Research, 10, 545-553.

Development of the bat mammary gland

In collaboration with John Rasweiler, SUNY Downstate Medical Center, and Richard Behringer, M. D. Anderson Cancer Center, we had the unique opportunity to investigate mammary glands of a different mammal: the short-tailed fruit bat Carollia perspicillata. The order of bats is very diverse and contains a large number of species (more than 1000) that exhibit a large variety of nursing and feeding habits that are reflected in their physiology. Their reproductive physiology has many features in common with humans. These include monovular, spontaneous ovulation with a functional luteal phase, a moderately long cycle terminated by true menstruation, giving birth to a single infant after gestation period of 113-119 days, and one pair of mammary glands. When the young are born they are extensively furred, have open eyes and weigh approximately 39% of the mother's mass. The females carry their growing young, both when resting and during foraging flights.

We compared mammary tissues from the fruit bat (Carollia perspicillata) and mouse (Mus musculus) using histological and immunohistochemical methods. In lactating and recently lactating specimens, bat tissue had significantly fewer adipocytes and more collagenous connective tissue than the mouse. The proteins Stat5a, keratin 5, Npt2b, and E-cadherin were all similarly localized in mouse and bat mammary tissues taken from lactating animals. This study demonstrates that while the epithelial compartment and the presence of differentiation markers are conserved between mouse and bat, differences exist in the stromal compartment. We speculate that this may be a consequence of the special requirements for the firm attachment of the young associated with their airborne life style.

References

Jennifer L. Evarts, John J. Rasweiler IV Richard R. Behringer, Lothar Hennighausen and Gertraud W. Robinson. A morphological and immunohistochemical comparison of mammary tissues from the short-tailed fruit bat (Carollia perspicillata) and the mouse. Biology of Reproduction in press.

Id2 controls proliferation and differentiation of mammary epithelium

Investigators: Keiko Miyoshi, Traudl Robinson

Collaborators: Peter Gruss, Barbara Meyer

PubMed search

References

1. Hennighausen, L. and Robinson, G.W. (2001) Signaling pathways in the mammary gland. Developmental Cell, 1, 467-475.