Definition of a critical spatiotemporal window within which primary cilia control midbrain dopaminergic neurogenesis

Abstract

Midbrain dopaminergic (mDA) neurons are generated in the ventral midbrain floor plate depending on Sonic Hedgehog (SHH) signaling for induction. Primary cilia transduce canonical SHH signals. Loss of intraflagellar transport protein IFT88, essential for ciliary function, disrupts SHH signaling in the ventral midbrain and results in the reduction in mDA progenitors and neurons. We investigate whether conditional inactivation of the kinesin motor protein KIF3A recapitulates phenotypes observed in conditional Ift88 mutants. Conditional Kif3a inactivation reduced the mDA progenitor domain size, but did not result in mDA neuron reduction, most likely because of a delayed loss of cilia and delayed inactivation of SHH signaling. We thereby define a precise spatiotemporal window within which primary cilia-dependent SHH signaling determines mDA fate.