Genetic and epigenetic mechanisms of gene regulation during lens development

Abstract

Recent studies demonstrated a number of links between chromatin structure, gene expression, extracellular signaling and cellular differentiation during lens development. Lens progenitor cells originate from a pool of common progenitor cells, the pre-placodal region (PPR) which is formed due to a complex exchange of extracellular signals between the neural plate, naïve ectoderm and mesendoderm. A specific commitment to the lens program over alternate choices such as the formation of olfactory epithelium or the anterior pituitary is manifested by the formation of a thickened surface ectoderm, the lens placode. Mouse lens progenitor cells are characterized by the expression of a complement of lens lineage-specific transcription factors including Pax6, Six3 and Sox2, controlled by FGF and BMP signaling, followed later by c-Maf, Mab21like1, Prox1 and FoxE3. Proliferation of lens progenitors together with their morphogenetic movements results in the formation of the lens vesicle. This transient structure, comprised of lens precursor cells, is polarized with its anterior cells retaining their epithelial morphology and proliferative capacity, whereas the posterior lens precursor cells initiate terminal differentiation forming the primary lens fibers. Lens differentiation is marked by expression and accumulation of crystallins and other structural proteins. The transcriptional control of crystallin genes is characterized by the reiterative use of transcription factors required for the establishment of lens precursors in combination with more ubiquitously expressed factors (e.g. AP-1, AP-2α, CREB and USF) and recruitment of histone acetyltransferases (HATs) CBP and p300, and chromatin remodeling complexes SWI/SNF and ISWI. These studies have poised the study of lens development at the forefront of efforts to understand the connections between development, cell signaling, gene transcription and chromatin remodeling.

MAPK1 is required for establishing the pattern of cell proliferation and for cell survival during lens development

“…Lens fiber cell differentiation is characterized by the temporal and spatially restricted expression of crystallin genes (Cvekl and Duncan, 2007). Our data showed that loss of MAPK1 did not affect crystallin gene expression (Fig.…”

The Orchestration of Mammalian Tissue Morphogenesis through a Series of Coherent Feed-forward Loops

“…lens, retina, cornea, iris, olfactory epithelium, forebrain, cerebellum, and pancreas) (41,43,44,79). It has been shown that Pax6 regulates the batteries of common target genes in distinct tissues, including the lens and neurons (57,80).…”

“…Thus, in contrast to the majority of sequencespecific DNA binding proteins that use a single DNA-binding domain that typically docks with 6 -10 bp of DNA, Pax6 can use ␤-sheets, PAI, linker, RED, and HD, and their various combinations to bind DNA. Although some important direct targets of Pax6 genes have been identified (41), a large body of work remains to be accomplished (42)(43)(44). Some transcription factors, especially those with multiple DNA-binding subdomains (e.g.…”

Pax6 is essential for lens fiber cell differentiation

“…Pax6 is known to bind, activate and repress crystallin gene expression in vitro and in vivo during early stages of development (Cvekl and Duncan, 2007;Cvekl et al, 2004). During the late stages of newt lens regeneration, which emulates normal lens development, Pax6 has been shown to be needed for LFC differentiation but not for crystallin maintenance (Madhavan et al, 2006).…”

“…Other proposed mechanisms include direct association of Pax6 with the centrosomes or mitotic chromosomes in proliferating cortical progenitors and cultured cells, respectively (Tamai et al, 2007;Zaccarini et al, 2007). The relevance of the above findings to Pax6 function in cell cycle regulation in the lens remains to be investigated.Pax6 is known to bind, activate and repress crystallin gene expression in vitro and in vivo during early stages of development (Cvekl and Duncan, 2007;Cvekl et al, 2004). During the late stages of newt lens regeneration, which emulates normal lens development, Pax6 has been shown to be needed for LFC differentiation but not for crystallin maintenance (Madhavan et al, 2006).…”