Biology subjects

Mongan, M.

Publications and source records attributed to Mongan, M..

3 recordsLinked to original sources

bioRxiv2024

Crosstalk of the MAP3K1 and EGFR pathways mediates gene-environment interactions that disrupt developmental tissue closure

Aberrant signal transduction pathways can adversely derail developmental processes. One such process is embryonic eyelid closure that requires MAP3K1. Map3k1 knockout mice have defective eyelid closure and an autosomal recessive eye-open at birth phenotype. In utero exposure to dioxin, a persistent environmental toxicant, causes the same eye defect in Map3k1+/- hemizygous but not wild type pups. Here we explore the mechanisms of Map3k1 (gene) and dioxin (environment) interactions (GxE) in the tissue closure defect. We show that, acting through the AHR, dioxin activates EGFR signaling, which in turn depresses MAP3K1-dependent JNK activity. This effect of dioxin is exacerbated by Map3k1 heterozygosity. Therefore, dioxin exposed Map3k1+/- embryonic eyelids have a marked reduction of JNK activity, accelerated differentiation and impeded polarization in the epithelial cells. Knocking out Ahr or Egfr in eyelid epithelium attenuates the open-eye defects in dioxin-treated Map3k1+/- pups, whereas knockout of Jnk1 and S1pr, encoding the S1P receptors upstream of the MAP3K1-JNK pathway, potentiates dioxin toxicity. Our novel findings suggest that dioxin and genes of the AHR, EGFR and S1P-MAP3K1-JNK pathways constitute a multifactorial mechanism underlying tissue closure abnormalities. Summary statementThe crosstalk between a global environmental pollutant and the pre-existing genetic conditions is mediated through interactive signaling pathways, resulting in anatomical tissue closure abnormalities in development.

developmental biology↗

bioRxiv2023

The Role of MAP3K1 in the Development of the Female Reproductive Tract

Mitogen-Activated Protein 3 Kinase 1 (MAP3K1) is a dynamic signaling molecule with a plethora of cell-type specific functions, most of which are yet to be understood. Here we describe a role for MAP3K1 in the development of female reproductive tract (FRT). MAP3K1 kinase domain-deficient (Map3k1{Delta}KD) females exhibit imperforate vagina, labor failure, and infertility. These defects correspond to a shunted Mullerian duct (MD), the principle precursor of the FRT, in embryos, while they manifest as a contorted caudal vagina with abrogated vaginal-urogenital sinus fusion in neonates. In epithelial cells, MAP3K1 acts through JNK and ERK to activate WNT, yet in vivo MAP3K1 is crucial for WNT activity in mesenchyme associated with the caudal MD. Expression of Wnt7b is high in wild type, but low in Map3k1 knockout MD epithelium and MAP3K1-deficient keratinocytes. Correspondingly, conditioned media derived from MAP3K1-competent epithelial cells activate TCF/Lef-luciferase reporter in fibroblasts, suggesting that MAP3K1-induced factors released from epithelial cells trans-activate WNT signaling in fibroblasts. Our results reveal a temporal-spatial and paracrine MAP3K1-WNT crosstalk contributing to MD caudal elongation and FRT development. HighlightsO_LIMAP3K1 deficient female mice exhibit imperforate vagina and infertility C_LIO_LILoss of MAP3K1 kinase activity impedes Mullerian duct (MD) caudal elongation and fusion with urogenital sinus (UGS) in embryogenesis C_LIO_LIThe MAP3K1-MAPK pathway up-regulates WNT signaling in epithelial cells C_LIO_LIMAP3K1 deficiency down-regulates Wnt7b expression in the MD epithelium and prevents WNT activity in mesenchyme of the caudal MD C_LI

developmental biology↗

bioRxiv2020

Sphingosine 1-phosphate activates the MAP3K1-JNK pathway to promote epithelial movement and morphogenesis

MAP 3 kinase 1 (MAP3K1) plays an essential role in embryonic eyelid development. It regulates epithelial morphogenesis through the spatial-temporal activation of Jun N-terminal kinases (JNKs), resulting in forward progression of the embryonic eyelid epithelial cells to enable eyelid closure. The developmental signals that activate the MAP3K1-JNK pathway are still unknown, mainly due to the lack of suitable keratinocyte lines to elucidate the mechanisms of pathway regulation. To address this deficiency, we developed a straightforward method for long-term culture of mouse keratinocytes in feeder-free conditions using Ca2+-free media. Cells grown under these conditions displayed characteristic basal epithelial morphology and keratin 14 expression, but did not form tight- or adherens-junctions. Increased extracellular Ca2+ levels restored the formation of cell-cell junctions. Using keratinocyte lines derived from wild type and Map3k1-deficient mice, we found that sphingosine 1-phosphate (S1P) activated the JNK-c-JUN pathways in a manner dependent on MAP3K1 kinase activity and that this MAP3K1-mediated signaling led to epithelial cell migration. The in vivo roles of this pathway were examined through crossing of genetic mutant mice. Loss-of-function of the S1P receptor (S1pr) 2/3 became haploinsufficient only when combined with Map3k1 and Jnk1 mutations such that the compound mutants displayed eyelid closure defects, suggesting these gene products cooperated in eye morphogenesis. Results of this work establish the S1PR-MAP3K1-JNK pathway as a crucial signaling mechanism for epithelial cell movement and morphogenesis.View Full Text

developmental biology↗