Zic4-lineage cells increase their contribution to visual thalamic nuclei during murine embryogenesis if they are homozygous or heterozygous for loss of Pax6 function

Abstract

Our aim was to study the mechanisms that contribute to the development of discrete thalamic nuclei during mouse embryogenesis (both sexes included). We characterized the expression of the transcription factor coding gene Zic4 and the distribution of cells that expressed Zic4 in their lineage. We used genetic fate mapping to show that Zic4-lineage cells mainly contribute to a subset of thalamic nuclei, in particular the lateral geniculate nuclei, which are crucial components of the visual pathway. We observed that almost all Zic4-lineage diencephalic progenitors express the transcription factor Pax6 at variable location-dependent levels. We used conditional mutagenesis to delete either one or both copies of Pax6 from Zic4-lineage cells. We found that Zic4-lineage cells carrying either homozygous or heterozygous loss of Pax6 contributed in abnormally high numbers to one or both of the main lateral geniculate nuclei. This could not be attributed to a change in cell production and was likely due to altered sorting of thalamic cells. Our results indicate that positional information encoded by the levels of Pax6 in diencephalic progenitors is an important determinant of the eventual locations of their daughter cells.

Significance Statement The development of the thalamus is a process in which cells that initially appear similar give rise to distinct cell groups called nuclei. How these nuclei form is poorly understood. We utilised a mouse model in which cells that express the gene Zic4 can be followed. We studied the consequences of knocking out either one or both copies of the gene encoding the Pax6 transcription factor in these Zic4-lineage cells. We found that these mutations had significant effects on the contribution of Zic4-lineage cells to specifically visual thalamic nuclei. This was not attributable to a change in Zic4-lineage cell production in mutants. Rather, we suggest that mutation of Pax6 affects the distribution of Zic4-lineage neurons to specific thalamic nuclei.