Derepression of sonic hedgehog signaling upon Gpr161 deletion unravels forebrain and ventricular abnormalities
| Autor: | Bandarigoda N. Somatilaka, Ashley G. Anderson, Genevieve Konopka, John M. Shelton, Saikat Mukhopadhyay, Veena Rajaram, Issei S. Shimada, Sun Hee Hwang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Neural Tube
Ependymal Cell Organogenesis Neuroepithelial Cells Mice Transgenic Nerve Tissue Proteins Biology Article Receptors G-Protein-Coupled Mice 03 medical and health sciences Prosencephalon 0302 clinical medicine Cell Movement Zinc Finger Protein Gli3 GLI3 medicine Animals Hedgehog Proteins Sonic hedgehog Molecular Biology Derepression 030304 developmental biology 0303 health sciences Neural tube Cell Biology Smoothened Receptor Hedgehog signaling pathway Cell biology Neuroepithelial cell medicine.anatomical_structure Forebrain biology.protein Neuroglia Gene Deletion 030217 neurology & neurosurgery Hydrocephalus Signal Transduction Developmental Biology |
| Zdroj: | Dev Biol |
| ISSN: | 0012-1606 |
| DOI: | 10.1016/j.ydbio.2019.03.011 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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