<i>Plag1</i>and<i>Plagl2</i>have overlapping and distinct functions in telencephalic development

Abstract

The <i>Plag</i> gene family has three members; <i>Plagl1/Zac1</i>, which is a tumor suppressor gene, and <i>Plag1</i> and <i>Plagl2</i>, which are proto-oncogenes. All three genes are known to be expressed in embryonic neural progenitors, and <i>Zac1</i> regulates proliferation, neuronal differentiation and migration in the developing neocortex. Here we examined the functions of <i>Plag1</i> and <i>Plagl2</i> in neocortical development. We first attempted, and were unable to generate, E12.5 <i>Plag1;Plagl2</i> double mutants, indicating that at least one <i>Plag1</i> or <i>Plagl2</i> gene copy is required for embryonic survival. We therefore focused on single mutants, revealing a telencephalic patterning defect in E12.5 <i>Plagl2</i> mutants and a proliferation/differentiation defect in <i>Plag1</i> mutant neocortices. Specifically, the ventral pallium, a dorsal telencephalic territory, expands into the ventral telencephalon in <i>Plagl2</i> mutants. In contrast, <i>Plag1</i> mutants develop normal regional territories, but neocortical progenitors proliferate less and instead produce more neurons. Finally, in gain-of-function studies, both <i>Plag1</i> and <i>Plagl2</i> reduce neurogenesis and increase BrdU-uptake, indicative of enhanced proliferation, but while <i>Plagl2</i> effects on proliferation are more immediate, <i>Plag1</i> effects are delayed. Taken together, we found that the <i>Plag</i> proto-oncogenes genes are essential regulators of neocortical development and although <i>Plag1</i> and <i>Plagl2</i> functions are similar, they do not entirely overlap. This article has an associated First Person interview with the first author of the paper.