The Genetics and Biology of FOXL2

<i>FOXL2</i> encodes a transcription factor that regulates a wide array of target genes including those involved in sex development, eyelid development, ovarian function and maintenance, genomic integrity as well as cellular pathways such as cell-cycle progression, proliferation, and apoptosis. The role of <i>FOXL2</i> has been widely studied in humans and animals. Consistent with its role in ovarian and eyelid development, over 100 germline variants in <i>FOXL2</i> are associated with blepharophimosis, ptosis, and epicanthus inversus syndrome in humans, an autosomal dominant condition characterised by ovarian dysgenesis/premature ovarian insufficiency, as well as defective eyelid development. Reflecting its role in apoptosis and proliferation, a somatic variant in <i>FOXL2</i> causes adult granulosa cell tumours in humans. Despite being widely studied and having clear relevance to human disease, much remains unknown about the genes FOXL2 regulates and how it exerts its wide-reaching effect on multiple organs. This review focuses on <i>FOXL2</i> and its varied roles as a transcription factor in sex determination, ovarian maintenance and function, eyelid development, genome integrity, and cell regulation, followed by discussion of the in vivo disruption of <i>FOXL2</i> in humans and other species.

Congenital Eyelid Anomalies: What General Physicians Need To Know

The eyelids are important structures that maintain the health of the ocular surface and have an important role in facial esthetics. Any interruption in eyelid development can lead to congenital eyelid deformities. Eyelid abnormalities in children may present at birth due to abnormal embryogenesis (congenital) or may occur at a later stage as the child matures (developmental). These abnormalities, in general, can be classified into three different categories depending on the location: malformation of the margins, malformation of the folds, and malformation of the position. Congenital and developmental eyelid abnormalities are among the most challenging problems encountered by ophthalmic reconstructive surgeons. Additional considerations include social factors regarding the patient’s self-awareness of their deformities and associated medical issues, which often coexist and maybe multisystem in nature. This article briefly reviews eyelid embryology, the most common congenital eyelid anomalies, and the management options available to address these conditions.

Sox Genes Show Spatiotemporal Expression during Murine Tongue and Eyelid Development

The tongue is a critical organ, involved in functions such as speaking, swallowing, mastication, and degustation. Although Sox genes are known to play critical roles in many biological processes, including organogenesis, the expression of the Sox family members during tongue development remains unclear. We therefore performed a comparative in situ hybridization analysis of 17 Sox genes (Sox1–14, 17, 18, and 21) during murine tongue development. Sox2, 4, 6, 8, 9, 10, 11, 12, and 21 were found to be expressed in the tongue epithelium, whereas Sox2, 4–6, 8–11, 13, and 21 showed expression in the mesenchyme of the developing tongue. Expression of Sox1, 4, 6, 8–12, and 21 were observed in the developing tongue muscle. Sox5 and 13 showed expression only at E12, while Sox1 expression was observed only on E18. Sox6, 8, 9, and 12 showed expression at several stages. Although the expression of Sox2, 4, 10, 11, and 21 was detected during all the four stages of tongue development, their expression patterns differed among the stages. We thus identified a dynamic spatiotemporal expression pattern of the Sox genes during murine tongue development. To understand whether Sox genes are involved in the development of other craniofacial organs through similar roles to those in tongue development, we also examined the expression of Sox genes in eyelid primordia, which also contain epithelium, mesenchyme, and muscle. However, expression patterns and timing of Sox genes differed between tongue and eyelid development. Sox genes are thus related to organogenesis through different functions in each craniofacial organ.

Genetic background-dependent role of Egr1 for eyelid development

EGR1 is an early growth response zinc finger transcription factor with broad actions, including in differentiation, mitogenesis, tumor suppression, and neuronal plasticity. Here we demonstrate that Egr1−/− mice on the C57BL/6 background have normal eyelid development, but back-crossing to BALB/c background for four or five generations resulted in defective eyelid development by day E15.5, at which time EGR1 was expressed in eyelids of WT mice. Defective eyelid formation correlated with profound ocular anomalies evident by postnatal days 1–4, including severe cryptophthalmos, microphthalmia or anophthalmia, retinal dysplasia, keratitis, corneal neovascularization, cataracts, and calcification. The BALB/c albino phenotype-associated Tyrc tyrosinase mutation appeared to contribute to the phenotype, because crossing the independent Tyrc-2J allele to Egr1−/− C57BL/6 mice also produced ocular abnormalities, albeit less severe than those in Egr1−/− BALB/c mice. Thus EGR1, in a genetic background-dependent manner, plays a critical role in mammalian eyelid development and closure, with subsequent impact on ocular integrity.