Prenatal alcohol exposure disrupts Shh pathway and primary cilia genes in the mouse neural tube
| Autor: | Eric W. Fish, Scott E. Parnell, Karen E. Boschen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
biology Cilium Neural tube medicine.disease Ciliopathies Joubert syndrome Cell biology 03 medical and health sciences Ciliopathy 0302 clinical medicine medicine.anatomical_structure GLI3 medicine biology.protein Sonic hedgehog 030217 neurology & neurosurgery 030304 developmental biology Morphogen |
| DOI: | 10.1101/649673 |
| Popis: | Neurulation-stage alcohol exposure (NAE; embryonic day [E] 8-10) is associated with midline craniofacial and CNS defects that likely arise from disruption of morphogen pathways, such as Sonic hedgehog (Shh). Notably, midline anomalies are also a hallmark of genetic ciliopathies such as Joubert syndrome. We tested whether NAE alters Shh pathway signaling and the number and function of primary cilia, organelles critical for Shh pathway transduction. Female C57BL/6J mice were administered two doses of alcohol (2.9 g/kg/dose) or vehicle on E9. Embryos were collected 6, 12, or 24 hr later, and changes to Shh, cell cycle genes, and primary cilia were measured in the rostroventral neural tube (RVNT). Within the first 24 hours post-NAE, reductions in Shh pathway and cell cycle gene expression and the ratio of Gli3 forms in the full-length activator state were observed. RVNT volume and cell layer width were reduced at 12 hr. In addition, expression of multiple cilia-related genes were observed at 6 hr post-NAE. As a further test of cilia gene-ethanol interaction, mice heterozygous forKif3aexhibited perturbed behavior during adolescence following NAE compared to vehicle-treated mice, andKif3aheterozygosity exacerbated the hyperactive effects of NAE on exploratory activity. These data demonstrate that NAE downregulates the Shh pathway in a region of the neural tube that gives rise to alcohol-sensitive brain structures and identifies disruption of primary cilia function, or a “transient ciliopathy”, as a possible cellular mechanism of prenatal alcohol pathogenesis. |
| Databáze: | OpenAIRE |
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