Oxidative stress-mediated apoptosis via the SLC23A2-ascorbic acid interaction contributes to cleft lip development

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• Non-syndromic cleft lip only (NSCLO) is a common congenital condition.
• The role of the SLC23A2 gene in cleft lip development was previously unreported.
• Gene-environment interactions are crucial in understanding CL/P etiology.

Purpose of the Study:

• To investigate the association between SLC23A2 and NSCLO.
• To explore the interaction of SLC23A2, reactive oxygen species (ROS), and ascorbic acid (AA) in lip development.
• To elucidate the molecular mechanism underlying SLC23A2's role in cleft lip formation.

Main Methods:

• Genome-wide association studies (GWAS) data analysis of SNPs in SLC23A2.
• In vitro studies using a human oral epithelial cell line (GMSM-K) to assess oxidative stress and apoptosis.
• In vivo studies using zebrafish models.
• RNA sequencing to explore molecular mechanisms.

Main Results:

• Ten SNPs in SLC23A2 were significantly correlated with NSCLO.
• Knockdown of SLC23A2 increased ROS and apoptosis, and decreased COL9A3 expression via the PI3K-Akt pathway.
• Ascorbic acid (AA) supplementation mitigated ROS and apoptosis in cells with functional SLC23A2 but not in SLC23A2-knockdown cells or zebrafish.

Conclusions:

• SLC23A2 is significantly associated with NSCLO.
• The interaction between SLC23A2, exogenous ROS, and AA plays a role in lip and craniofacial development.
• This interaction influences cellular levels of ROS and apoptosis, impacting developmental processes.