Lkb1 controls expansion and folding of the cerebellar cortex

Abstract

Cerebellar growth and foliation require the Hedgehog-driven proliferation of granule cell precursors (GCPs) in the external granule layer (EGL). However, that increased or extended GCP proliferation generally does not elicit ectopic folds suggests that additional cellular mechanisms control cortical expansion and foliation during cerebellar development. Here, we find that genetic loss of the serine-threonine kinase Liver Kinase B1 (Lkb1) in GCPs increased cerebellar cortical size and foliation independent of changes in proliferation or Hedgehog signaling. Our results suggest that Lkb1 regulates cortical expansion and foliation by orienting mitotic GCP divisions perpendicular to the cerebellar surface. Consequently, genetic loss of Lkb1 from GCPs randomized the orientation of GCP divisions, effectively increasing the proportion of cells dividing parallel to the cerebellar surface. We propose that increased parallel divisions expanded cortical area by positioning GCPs next to, rather than on top of, one another following mitosis. Notably, alterations in the plane of division did not alter GCP differentiation. Additionally, we find that Lkb1 is important for radial migration of post-mitotic GCPs. Cortical expansion, increased foliation, and altered migration were independent of the well-documented Lkb1 substrate AMP-activated Kinase (AMPK). Taken together, our results reveal an important role for Lkb1 during cerebellar development and uncover oriented cell divisions as a previously unappreciated determinant of cerebellar cortical size and folding.