Derepression of sonic hedgehog signaling upon Gpr161 deletion unravels forebrain and ventricular abnormalities

Dev Biol. 2019 Jun 1;450(1):47-62. doi: 10.1016/j.ydbio.2019.03.011. Epub 2019 Mar 23.


Inverse gradients of transcriptional repressors antagonize the transcriptional effector response to morphogens. However, the role of such inverse regulation might not manifest solely from lack of repressors. Sonic hedgehog (Shh) patterns the forebrain by being expressed ventrally; however, absence of antagonizing Gli3 repressor paradoxically cause insufficient pathway activation. Interestingly, lack of the primary cilia-localized G-protein-coupled receptor, Gpr161 increases Shh signaling in the mouse neural tube from coordinated lack of Gli3 repressor and Smoothened-independent activation. Here, by deleting Gpr161 in mouse neuroepithelial cells and radial glia at early mid-gestation we detected derepression of Shh signaling throughout forebrain, allowing determination of the pathophysiological consequences. Accumulation of cerebrospinal fluid (hydrocephalus) was apparent by birth, although usual causative defects in multiciliated ependymal cells or aqueduct were not seen. Rather, the ventricular surface was expanded (ventriculomegaly) during embryogenesis from radial glial overproliferation. Cortical phenotypes included polymicrogyria in the medial cingulate cortex, increased proliferation of intermediate progenitors and basal radial glia, and altered neocortical cytoarchitectonic structure with increased upper layer and decreased deep layer neurons. Finally, periventricular nodular heterotopia resulted from disrupted neuronal migration, while the radial glial scaffold was unaffected. Overall, suppression of Shh pathway during early mid-gestation prevents ventricular overgrowth, and regulates cortical gyration and neocortical/periventricular cytoarchitecture.

Keywords: Gpr161; Hydrocephalus; Periventricular heterotopia; Polymicrogyria; Primary cilia; Sonic hedgehog.

Publication types

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

MeSH terms

  • Animals
  • Cell Movement
  • Gene Deletion
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Hydrocephalus* / embryology
  • Hydrocephalus* / genetics
  • Hydrocephalus* / pathology
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Tube / abnormalities
  • Neural Tube / embryology
  • Neuroepithelial Cells / metabolism
  • Neuroepithelial Cells / pathology
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Organogenesis*
  • Prosencephalon* / abnormalities
  • Prosencephalon* / embryology
  • Receptors, G-Protein-Coupled / deficiency*
  • Signal Transduction*
  • Smoothened Receptor / genetics
  • Smoothened Receptor / metabolism
  • Zinc Finger Protein Gli3 / genetics
  • Zinc Finger Protein Gli3 / metabolism


  • GPR161 protein, mouse
  • Gli3 protein, mouse
  • Hedgehog Proteins
  • Nerve Tissue Proteins
  • Receptors, G-Protein-Coupled
  • Shh protein, mouse
  • Smo protein, mouse
  • Smoothened Receptor
  • Zinc Finger Protein Gli3