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© The Rockefeller University Press, 0021-9525/1998//1497 $5.00
The Journal of Cell Biology, Volume 140, Number 6, , 1998 1497-1509

Article

A Critical Temporal Requirement for the Retinoblastoma Protein Family During Neuronal Determination



Ruth S. Slack, Hiba El-Bizri, Josée Wong, Daniel J. Belliveau, and Freda D. Miller

Center for Neuronal Survival, Montreal Neurological Institute, McGill University, 3801 rue University, Montreal, Canada H3A 2B4

In this report, we have examined the requirement for the retinoblastoma (Rb) gene family in neuronal determination with a focus on the developing neocortex. To determine whether pRb is required for neuronal determination in vivo, we crossed the Rb–/– mice with transgenic mice expressing β-galactosidase from the early, panneuronal T{alpha}1 {alpha}-tubulin promoter (T{alpha}1:nlacZ). In E12.5 Rb–/– embryos, the T{alpha}1:nlacZ transgene was robustly expressed throughout the developing nervous system. However, by E14.5, there were perturbations in T{alpha}1:nlacZ expression throughout the nervous system, including deficits in the forebrain and retina. To more precisely define the temporal requirement for pRb in neuronal determination, we functionally ablated the pRb family in wild-type cortical progenitor cells that undergo the transition to postmitotic neurons in vitro by expression of a mutant adenovirus E1A protein. These studies revealed that induction of T{alpha}1:nlacZ did not require proteins of the pRb family. However, in their absence, determined, T{alpha}1:nlacZ-positive cortical neurons underwent apoptosis, presumably as a consequence of "mixed signals" deriving from their inability to undergo terminal mitosis. In contrast, when the pRb family was ablated in postmitotic cortical neurons, there was no effect on neuronal survival, nor did it cause the postmitotic neurons to reenter the cell cycle. Together, these studies define a critical temporal window of requirement for the pRb family; these proteins are not required for induction of neuronal gene expression or for the maintenance of postmitotic neurons, but are essential for determined neurons to exit the cell cycle and survive.

Abbreviations used in this paper: MOI, multiplicity of infection; Rb, retinoblastoma.

The adenovirus recombinant vectors Ad5CA17lacZ was kindly provided by Dr. Frank Graham (McMaster University, Hamilton, Ontario). Adenovirus mutant E1A [1101] and M73 antibody were gifts from Dr. Phil Branton (McGill University, Montreal, Canada). We thank Dr. Anirvan Ghosh and Jim Fawcett for assistance with cortical progenitor cell cultures, and Dr. Andrew Gloster for assistance with analysis of T{alpha}1:nlacZ transgene expression in Rb-deficient embryos. The technical assistance of Audrey Speelman and Rahul Varma is gratefully acknowledged.

R.S. Slack and H. El-Bizri contributed equally to this work.

Dr. Slack's current address is Neuroscience Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Canada K1H 8M5. Dr. Belliveau's current address is Department of Anatomy and Cell Biology, University of Western Ontario, Medical Sciences Building, London, Canada M6A 5C1.


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