Abnormal Epithelial Cell Polarity and Ectopic Epidermal Growth Factor Receptor (EGFR) Expression Induced in Emx2 KO Embryonic Gonads

Abstract

The gonadal primordium first emerges as a thickening of the embryonic coelomic epithelium, which has been thought to migrate mediodorsally to form the primitive gonad. However, the early gonadal development remains poorly understood. Mice lacking the paired-like homeobox gene Emx2 display gonadal dysgenesis. Interestingly, the knockout (KO) embryonic gonads develop an unusual surface accompanied by aberrant tight junction assembly. Morphological and in vitro cell fate mapping studies showed an apparent decrease in the number of the gonadal epithelial cells migrated to mesenchymal compartment in the KO, suggesting that polarized cell division and subsequent cell migration are affected. Microarray analyses of the epithelial cells revealed significant up-regulation of Egfr in the KO, indicating that Emx2 suppresses Egfr gene expression. This genetic correlation between the two genes was reproduced with cultured M15 cells derived from mesonephric epithelial cells. Epidermal growth factor receptor signaling was recently shown to regulate tight junction assembly through sarcoma viral oncogene homolog tyrosine phosphorylation. We show through Emx2 KO analyses that sarcoma viral oncogene homolog tyrosine phosphorylation, epidermal growth factor receptor tyrosine phosphorylation, and Egfr expression are up-regulated in the embryonic gonad. Our results strongly suggest that Emx2 is required for regulation of tight junction assembly and allowing migration of the gonadal epithelia to the mesenchyme, which are possibly mediated by suppression of Egfr expression.

Molecular mechanisms involved in mammalian primary sex determination

“…1A; Eggers & Sinclair 2012, Hu et al 2013. Homozygous deletion of any one of these genes results in progressive degeneration of the emerging differentiated somatic cell lineages and disruption of the subtle structure of the genital ridge (Gao et al 2006, Kusaka et al 2010, Manuylov et al 2011, Hu et al 2013.…”

“…In Emx2-null mice, the urogenital system, including kidney, ureters, genital ridge, and genital tracts, is absolutely absent and the formation of the ureteric bud is disrupted (Miyamoto et al 1997). Early stages of Emx2-knockout embryonic gonads display abnormal cell proliferation and disorganized migration of gonadal epithelial cells to the mesenchymal compartment (Kusaka et al 2010). The aberrant tight-junction assembly of the gonadal epithelia cells and upregulated expression of Egfr in Emx2-KO embryonic gonads …”

“…1B; Kusaka et al 2010). The expression of Sf1 and aristaless-related homeobox (Arx) is absent in the Emx2-KO gonads at E11.5, indicating that Emx2 may directly or indirectly coordinate the expression of Sf1 and Arx in the developing gonads, while the expression patterns of other genes, including Gata4, Wt1, and Lhx9, are intact in the Emx2-KO gonads (Kusaka et al 2010).…”

“…1B; Kusaka et al 2010). The expression of Sf1 and aristaless-related homeobox (Arx) is absent in the Emx2-KO gonads at E11.5, indicating that Emx2 may directly or indirectly coordinate the expression of Sf1 and Arx in the developing gonads, while the expression patterns of other genes, including Gata4, Wt1, and Lhx9, are intact in the Emx2-KO gonads (Kusaka et al 2010). Recent studies on the Pax2 C/K ; Emx2 C/K mice embryos have revealed that Pax2 may directly regulate the Emx2 expression in the Wolffian duct, and Pax2 coordinates the ureter and kidney development (Boualia et al 2011).…”

“…Transcription factor -Aberrant tight junction assembly, failure in genital ridge formation (LOF) Kusaka et al (2010) …”