Mouse Disabled 1 Regulates the Nuclear Position of Neurons in a Drosophila Eye Model

Abstract

Nucleokinesis has recently been suggested as a critical regulator of neuronal migration. Here we show that Disabled 1 (Dab1), which is required for neuronal positioning in mammals, regulates the nuclear position of postmitotic neurons in a phosphorylation-site dependent manner. Dab1 expression in the Drosophila visual system partially rescues nuclear position defects caused by a mutation in the Dynactin subunit Glued. Furthermore, we observed that a loss-of-function allele of amyloid precursor protein (APP)-like, a kinesin cargo receptor, enhanced the severity of a Dab1 overexpression phenotype characterized by misplaced nuclei in the adult retina. In mammalian neurons, overexpression of APP reduced the ability of Reelin to induce Dab1 tyrosine phosphorylation, suggesting an antagonistic relationship between APP family members and Dab1 function. This is the first evidence that signaling which regulates Dab1 tyrosine phosphorylation determines nuclear positioning through Dab1-mediated influences on microtubule motor proteins in a subset of neurons.

We are grateful to Ed Giniger for comments on the manuscript and to Kalpana White, Paul Garrity, Kyung-Tai Min, and Jessica Whited for advice and the gift of Drosophila lines. We thank the following individuals for reagents that were made available through the Developmental Studies Hybridoma Bank (DSHB): S. Benzer (24B10 antibody), G. Rubin (7E8A10 antibody), and M. Klymkowsky (E7 antibody). DSHB was developed under the auspices of the NICHD and is maintained by The University of Iowa, Department of Biological Sciences, Iowa City, IA.

None of the authors has any financial interests related to this work.

This work was supported by NINDS intramural funds and an HHMI-NIH research scholarship to P.G.O.