Schizophrenia-related microdeletion causes defective ciliary motility and brain ventricle enlargement via microRNA-dependent mechanisms in mice

Nat Commun. 2020 Feb 14;11(1):912. doi: 10.1038/s41467-020-14628-y.

Abstract

Progressive ventricular enlargement, a key feature of several neurologic and psychiatric diseases, is mediated by unknown mechanisms. Here, using murine models of 22q11-deletion syndrome (22q11DS), which is associated with schizophrenia in humans, we found progressive enlargement of lateral and third ventricles and deceleration of ciliary beating on ependymal cells lining the ventricular walls. The cilia-beating deficit observed in brain slices and in vivo is caused by elevated levels of dopamine receptors (Drd1), which are expressed in motile cilia. Haploinsufficiency of the microRNA-processing gene Dgcr8 results in Drd1 elevation, which is brought about by a reduction in Drd1-targeting microRNAs miR-382-3p and miR-674-3p. Replenishing either microRNA in 22q11DS mice normalizes ciliary beating and ventricular size. Knocking down the microRNAs or deleting their seed sites on Drd1 mimicked the cilia-beating and ventricular deficits. These results suggest that the Dgcr8-miR-382-3p/miR-674-3p-Drd1 mechanism contributes to deceleration of ciliary motility and age-dependent ventricular enlargement in 22q11DS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Ventricles / metabolism*
  • Chromosome Deletion
  • Cilia / genetics
  • Cilia / physiology*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Receptors, Dopamine / genetics
  • Receptors, Dopamine / metabolism
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism
  • Schizophrenia / physiopathology

Substances

  • Dgcr8 protein, mouse
  • MIRN674 microRNA, mouse
  • MicroRNAs
  • RNA-Binding Proteins
  • Receptors, Dopamine
  • microRNA 382, mouse