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

Issei S. Shimada, Bandarigoda N. Somatilaka, Sun Hee Hwang, Ashley G. Anderson, John M. Shelton, Veena Rajaram, Genevieve Konopka, Saikat Mukhopadhyay

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)47-62
Number of pages16
JournalDevelopmental Biology
Volume450
Issue number1
DOIs
StatePublished - Jun 1 2019

Fingerprint

Hedgehogs
Prosencephalon
Neuroglia
Periventricular Nodular Heterotopia
Neuroepithelial Cells
Pregnancy
Neural Tube
Cilia
Gyrus Cinguli
Hydrocephalus
G-Protein-Coupled Receptors
Embryonic Development
Cerebrospinal Fluid
Parturition
Phenotype
Neurons

Keywords

  • Gpr161
  • Hydrocephalus
  • Periventricular heterotopia
  • Polymicrogyria
  • Primary cilia
  • Sonic hedgehog

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Derepression of sonic hedgehog signaling upon Gpr161 deletion unravels forebrain and ventricular abnormalities. / Shimada, Issei S.; Somatilaka, Bandarigoda N.; Hwang, Sun Hee; Anderson, Ashley G.; Shelton, John M.; Rajaram, Veena; Konopka, Genevieve; Mukhopadhyay, Saikat.

In: Developmental Biology, Vol. 450, No. 1, 01.06.2019, p. 47-62.

Research output: Contribution to journalArticle

Shimada, Issei S. ; Somatilaka, Bandarigoda N. ; Hwang, Sun Hee ; Anderson, Ashley G. ; Shelton, John M. ; Rajaram, Veena ; Konopka, Genevieve ; Mukhopadhyay, Saikat. / Derepression of sonic hedgehog signaling upon Gpr161 deletion unravels forebrain and ventricular abnormalities. In: Developmental Biology. 2019 ; Vol. 450, No. 1. pp. 47-62.
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