Lurcher, Cell Death and the Cell Cycle

  • N. Heintz
  • L. Feng
  • J. Gubbay
  • S. Cheng
  • J. Zuo
  • P. L. De Jager
  • D. J. Norman
Part of the Research and Perspectives in Alzheimer’s Disease book series (ALZHEIMER)

Summary

The mouse neurologic mutant Lurcher carries a semidominant genetic lesion that results in severe neurologic dysfunction (Philips 1960). Classical studies have established that the Lurcher mutation results in cell autonomous death of cerebellar Purkinje cells beginning in the second postnatal week (Caddy and Biscoe 1975). We have examined the expression of terminal markers for Purkinje cell differentiation, including the Kv3.3b potassium channel (Goldman-Wohl et al. 1994), and demonstrated that they are expressed prior to cell death in Lurcher animals. Detailed genetic studies have allowed identification of Lc/Lc homozygotes prior to their death in the first postnatal day, and histologic studies of these animals indicate that Lurcher homozygotes are missing large neurons in several hindbrain nuclei. These studies establish that the Lurcher gene causes dose-dependent cell death of specific neuronal populations following their differentiation in the cerebellum and hindbrain.

In considering possible causes for cell loss in Lc mice, I speculated that gross perturbations in signal transduction within terminally differentiated neurons can cause reactivation of programmed cell death (Heintz 1993). This process is formally analogous to the activation of oncogenes in stem cells, which perturb signal transduction sufficiently to alter cell growth control, eventually leading to transformation. We suggest that this type of activation, or failure in cellular homeostasis, in differentiated neurons can only result in programmed cell death because this is the only efferent pathway available to cells that have permanently exited the cell cycle. As an initial indication that this idea may pertain in the case of the Lurcher disease, we examined the mode of death of Purkinje cells in mutant animals. We found that the Lurcher gene causes activation of programmed cell death in Purkinje cells, and we suggest that this may be typical of many neurologic diseases. Cloning of the Lurcher gene product will allow identification of the molecules and mechanisms that participate in this process, providing a first test of this general idea.

Keywords

Electrophoresis Germinal Macromolecule Biotin dNTP 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • N. Heintz
    • 1
  • L. Feng
  • J. Gubbay
  • S. Cheng
  • J. Zuo
  • P. L. De Jager
  • D. J. Norman
  1. 1.Howard Hughes Medical InstituteThe Rockefeller UniversityNew YorkUSA

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