WDR5-HOTTIP Histone Modifying Complex Regulates Neural Migration and Dendrite Polarity of Pyramidal Neurons via Reelin Signaling

WD-repeat domain 5 (WDR5), a core component of histone methyltransferase complexes, is associated with Kabuki syndrome and Kleefstra syndrome that feature intellectual disability and neurodevelopmental delay. Despite its critical status in gene regulation and neurological disorders, the role of WDR5 in neural development is unknown. Here we show that WDR5 is required for normal neuronal placement and dendrite polarization in the developing cerebral cortex. WDR5 knockdown led to defects in both entry into the bipolar transition of pyramidal neurons within the intermediate zone and radial migration into cortical layers. Moreover, WDR5 deficiency disrupted apical and basal polarity of cortical dendrites. Aberrant dendritic spines and synapses accompanied the dendrite polarity phenotype. WDR5 deficiency reduced expression of reelin signaling receptors, ApoER and VdldR, which were associated with abnormal H3K4 methylation and H4 acetylation on their promoter regions. Finally, an lncRNA, HOTTIP, was found to be a partner of WDR5 to regulate dendritic polarity and reelin signaling via histone modification. Our results demonstrate a novel role for WDR5 in neuronal development and provide mechanistic insights into the neuropathology associated with histone methyltransferase dysfunction.