The developing lens transcriptome depends upon a counterbalance of Fgfr2- and Pten-regulated downstream signaling and transcription factor targets

ABSTRACT: FGFR signaling plays important roles in development and disease pathogenesis. FGFR activation initiates phosphorylation-driven signaling cascades, most notably the RAS-RAF-MEK-ERK cascade and the PI3K-AKT cascade. PTEN antagonizes FGFR signaling by reducing both AKT and ERK activation. Lenses lacking FGFR2 exhibit lower levels of ERK and AKT phosphorylation accompanied by abnormally small lenses, widespread apoptosis, and defective fiber cell differentiation. In contrast, simultaneous deletion of both Fgfr2 and Pten restores ERK and AKT activation levels as well as lens size, cell survival and several aspects of fiber cell differentiation. A transcriptomic analysis of mouse lenses lacking Fgfr2, Pten or both Fgfr2 and Pten revealed molecular mechanisms that might explain how FGFR2 and PTEN signaling interact during development. The FGFR2-deficient lens transcriptome suggested an overall loss of fiber cell identity with deregulated expression of 1,448 genes, nearly 60% of which returned to normal expression levels in lenses lacking both Fgfr2 and Pten. A specific set of parameters based on expression levels in each genotype identified 68 high priority candidate genes. The homeobox transcription factor, NKX6-1, encoded by one of these genes, had at least one binding motif in the putative promoters of 53 of these 68 genes. Furthermore, NKX6-1 activated the expression of the high priority candidate Rasgrp1, a RAS-activating guanine nucleotide exchange factor. Together, these data suggest a novel regulatory module in which NKX6-1 activates the expression of Rasgrp1 to restore the balance of ERK and AKT activation in the absence of both FGFR2 and PTEN.

ORGANISM(S): Mus musculus

PROVIDER: GSE132945 | GEO | 2020/02/28

REPOSITORIES: GEO