A high level of KLF12 causes folic acid-resistant neural tube defects by activating the Shh signalling pathway in mice

Biol Reprod. 2021 Jun 8:ioab111. doi: 10.1093/biolre/ioab111. Online ahead of print.ABSTRACTAlthough 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 foetuses 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 foetuses. The RNA-seq results showed that a high level of KLF12 caused NTDs in mice via overactivating the sonic hedgehog (Shh) signalling pathway, leading to the upregulation of patched 1, GLI-Krüppel family member GLI1, hedgehog-interacting protein, etc., while FA metabolism-related enzymes did not express differently. PF-5274857, an antagonist of the Shh signalling 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.PMID:34104947 | DOI:10.1093/biolre/ioab111
Source: Biology of Reproduction - Category: Reproduction Medicine Authors: Source Type: research