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A high level of KLF12 causes folic acid-resistant neural tube defects by activating the Shh signaling pathway in miceā
- Source :
- Biology of Reproduction. 105:837-845
- Publication Year :
- 2021
- Publisher :
- Oxford University Press (OUP), 2021.
-
Abstract
- Although adequate periconceptional folic acid (FA) supplementation has reduced the occurrence of pregnancies affected by neural tube defects (NTDs), the mechanisms underlying FA-resistant NTDs are poorly understood, and thus NTDs still remain a global public health concern. A high level of Kruppel-like factor 12 (KLF12) exerts deleterious effects on heath in most cases, but evidence for its roles in development has not been published. We observed KLF12-overexpressing mice showed disturbed neural tube development. KLF12-overexpressing fetuses died in utero at approximately 10.5 days post-coitus, with 100% presenting cranial NTDs. Neither FA nor formate promoted normal neural tube closure in mutant fetuses. The RNA-seq results showed that a high level of KLF12 caused NTDs in mice via overactivating the sonic hedgehog (Shh) signaling pathway, leading to the upregulation of patched 1, GLI-Kruppel family member GLI1, hedgehog-interacting protein, etc., whereas FA metabolism-related enzymes did not express differently. PF-5274857, an antagonist of the Shh signaling pathway, significantly promoted dorsolateral hinge point formation and partially rescued the NTDs. The regulatory hierarchy between a high level of KLF12 and FA-resistant NTDs might provide new insights into the diagnosis and treatment of unexplained NTDs in the future. Summary sentence A high level of KLF12 in the early stage of embryogenesis caused FA-resistant neural tube defects by overactivating the Shh signaling pathway, which could be partially rescued by PF-5274857.
- Subjects :
- Male
0301 basic medicine
Patched
congenital, hereditary, and neonatal diseases and abnormalities
Kruppel-Like Transcription Factors
Mice
03 medical and health sciences
Folic Acid
0302 clinical medicine
Downregulation and upregulation
GLI1
medicine
Animals
Hedgehog Proteins
Neural Tube Defects
Sonic hedgehog
Fetus
biology
Embryogenesis
Neural tube
Cell Biology
General Medicine
Cell biology
030104 developmental biology
medicine.anatomical_structure
Reproductive Medicine
030220 oncology & carcinogenesis
biology.protein
Female
Signal transduction
Signal Transduction
Subjects
Details
- ISSN :
- 15297268 and 00063363
- Volume :
- 105
- Database :
- OpenAIRE
- Journal :
- Biology of Reproduction
- Accession number :
- edsair.doi.dedup.....6325234054d01f1bc163eb15c10f7d97