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8 June 2021 A high level of KLF12 causes folic acid-resistant neural tube defects by activating the Shh signaling pathway in mice
Yang Liu, Qiong Yuan, Zhilong Wang, Lijun Ding, Na Kong, Jingyu Liu, Yali Hu, Yang Zhang, Chaojun Li, Guijun Yan, Yue Jiang, Haixiang Sun
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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 Krüppel-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-Krüppel 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.

© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Yang Liu, Qiong Yuan, Zhilong Wang, Lijun Ding, Na Kong, Jingyu Liu, Yali Hu, Yang Zhang, Chaojun Li, Guijun Yan, Yue Jiang, and Haixiang Sun "A high level of KLF12 causes folic acid-resistant neural tube defects by activating the Shh signaling pathway in mice," Biology of Reproduction 105(4), 837-845, (8 June 2021). https://doi.org/10.1093/biolre/ioab111
Received: 16 March 2021; Accepted: 2 June 2021; Published: 8 June 2021
KEYWORDS
FA-resistant NTDs
KLF12
PF-5274857
Shh signaling pathway
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