MicroRNAs and Gene Regulatory Networks Related to Cleft Lip and Palate

Abstract

Cleft lip and palate is one of the most common congenital birth defects and has a complex etiology. Either genetic or environmental factors, or both, are involved at various degrees, and the type and severity of clefts vary. One of the longstanding questions is how environmental factors lead to craniofacial developmental anomalies. Recent studies highlight non-coding RNAs as potential epigenetic regulators in cleft lip and palate. In this review, we will discuss microRNAs, a type of small non-coding RNAs that can simultaneously regulate expression of many downstream target genes, as a causative mechanism of cleft lip and palate in humans and mice.

Keywords: cleft lip; cleft palate; craniofacial development; environmental factor; microRNA.

Figure 1

Major cell types in the palate. The majority of the mesenchyme of the lip and palate is composed of cranial neural crest (CNC) cells, which can form both bone and connective tissues. Epithelial cells develop into nasal and oral epithelial cells, characterized by different functions and gene expression profiles.

Figure 2

The cause of cleft lip with/without cleft palate (CL/P) and cleft palate only (CPO). Both genetic and environmental factors can contribute to the etiology of clefts. Environmental factors can alter the epigenetic status, including miRNA expression, DNA methylation, and chromatin modification. These epigenetic factors can be categorized into two groups: intrinsic and extrinsic factors. Chemical-induced cleft models are useful to study the contribution of pathogenic miRNAs to cleft lip and cleft palate.

Figure 3

Summary of the miRNAs and genes associated with cleft lip in humans and mice. Phenytoin is a known inducer of cleft lip in mice. It inhibits cell proliferation in cultured cells through induction of pathogenic miR-196a-5p, which suppress expression of genes related to cleft lip. CL, cleft lip.

Figure 4

Summary of miRNAs and genes related to cleft palate in humans and mice. Through bioinformatic analysis for gene expression datasets and genes related to cleft palate, several miRNAs related to cleft palate are suggested to be pathogenic miRNAs. Many miRNAs among them have been validated in cultured cells and/or chemical-induced cleft palate mouse models. CL, cleft lip; CP cleft palate (including CPO and CLP).