The Early Isoform of Disabled-1 Functions Independently of Reelin-Mediated Tyrosine Phosphorylation in Chick Retina

Abstract

The Reelin-Disabled-1 (Dab1) signaling pathway plays a key role in the positioning of neurons during brain development. Two alternatively spliced Dab1 isoforms have been identified in chick retina and brain: Dab1-E, expressed at early stages of development, and Dab1-L (commonly referred to as Dab1), expressed at later developmental stages. The well-studied Dab1-L serves as an adaptor protein linking Reelin signal to its downstream effectors; however, nothing is known regarding the role of Dab1-E. Here we show that Dab1-E is primarily expressed in proliferating retinal progenitor cells whereas Dab1-L is found exclusively in differentiated neuronal cells. In contrast to Dab1-L, which is tyrosine phosphorylated upon Reelin stimulation, Dab1-E is not tyrosine phosphorylated and may function independently of Reelin. Knockdown of Dab1-E in chick retina results in a significant reduction in the number of proliferating cells and promotes ganglion cell differentiation. Our results demonstrate a role for Dab1-E in the maintenance of the retinal progenitor pool and determination of cell fate.

Supplemental material for this article may be found at http://mcb.asm.org/.

We are grateful to Jonathan A. Cooper for the anti-Dab1 (B3) antibody, Tom Curran for the pCrl-Reelin construct, Joachim Herz for the ApoER2 antibody, and Jianxun Han for the γ-secretase inhibitor DAPT. We thank Xuejun Sun and Gerry Barron for their help with cell scoring using the Metamorph software program.

This work was supported by the Canadian Institutes of Health Research. Z.G. is supported by an Alberta Heritage Foundation for Medical Research studentship and a Dissertation Fellowship from the University of Alberta.