Abstract
Folic acid deficiency during pregnancy causes birth neurocristopathic malformations resulting from aberrant development of neural crest cells. The Reduced folate carrier (RFC) is a membrane-bound receptor for facilitating transfer of reduced folate into the cells. RFC knockout mice are embryonic lethal and develop multiple malformations, including neurocristopathies. Here we show that XRFC is specifically expressed in neural crest tissues in Xenopus embryos and knockdown of XRFC by specific morpholino results in severe neurocristopathies. Inhibition of RFC blocked the expression of a series of neural crest marker genes while overexpression of RFC or injection of 5-methyltetrahydrofolate expanded the neural crest territories. In animal cap assays, knockdown of RFC dramatically reduced the mono- and trimethyl-Histone3-K4 levels and co-injection of the lysine methyltransferase hMLL1 largely rescued the XRFC morpholino phenotype. Our data revealed that the RFC mediated folate metabolic pathway likely potentiates neural crest gene expression through epigenetic modifications.
Highlights
Neural crest (NC) is a multipotent cell population which originates at the border between the neural plate and epidermis during vertebrate development
We examined the temporal and spatial expression pattern of XRFC during early Xenopus embryogenesis by Reverse transcription and polymerase chain reaction (RT-PCR) and wholemount in situ hybridization
The expression pattern of XRFC overlaps with the neural crest territories, including the neural plate border, branchial arches, somites and the head mescenchyme
Summary
Neural crest (NC) is a multipotent cell population which originates at the border between the neural plate and epidermis during vertebrate development Later on, these cells migrate to various places throughout the body and give rise to various tissues, including craniofacial bones and cartilages, melanocytes, cardiac structures and peripheral nervous system [1]. These signals control the broad expression of a set of transcription factors at the neural plate border region, including Pax, Msx and Zic1 These neural plate border specifiers further turn on the expression of a group of genes in the emerging neural crest cells, including Snail, Snail, FoxD3, Sox, Sox, and Twist. These neural crest genes are extensively cross-regulated and many of them have been shown to be necessary and/or sufficient for the expression of many other genes
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