Homeobox Gene Program

The blueprint for the embryonic program involves the homeobox genes (HOX). These genes are so named because they contain a distinctive and highly conserved segment of DNA, approximately 180 base pairs long, that encodes a conserved 60–amino acid sequence constituting the homeodomain. The homeodomain provides a protein with specific DNA-binding capabilities.

The function of HOX genes as master regulators arises from the ability of these genes to regulate expression of downstream genes through homeodomain binding to DNA promoter sequences, wherein they act as switches of gene transcription. Each set of switches drives a particular cell fate, and transcriptional cascades of these switches lead to the development of different tissues and organs.

As expected, specific HOX genes are crucial for development of the eye (Fig 4-18). The paired box 6 gene, PAX6, in particular, appears to be a master switch for eye development. The PAX6 transcription factor is expressed in a band in the anterior neural plate, very early in the primordial eye field, and ectopic expression of PAX6 can lead to ectopic eyes and aniridia, Peters anomaly, coloboma, and microphthalmia. The following HOX genes also play key roles in development of the eye, and mutations in these genes have been reported in patients with the conditions given within parentheses: paired box 2, PAX2 (renal coloboma syndrome), retina and anterior neural fold homeobox gene, RAX (eg, microphthalmia), and paired like homeodomain 2, PITX2 (eg, Peters anomaly, Axenfeld-Rieger syndrome).

Figure 4-18 Scanning electron micrograph of an optic vesicle (dorsal is at top of image; optic stalk cavity to the left). The section is color coded to indicate the homeobox genes and diffusible extracellular factors expressed in a particular location that predetermine tissue development. Red = retinal pigment epithelium; green = retina; blue = lens; yellow = optic stalk. FGF = fibroblast growth factor; LHX2 = LIM homeobox 2 gene; MITF = microphthalmiaassociated transcription factor; OTX2 = orthodenticle homeobox 2 gene; PAX2 = paired box 2 gene; PAX6 = paired box 6 gene; Shh = sonic hedgehog; VSX2 = visual system homeobox 2 gene; Wnt = Wnt transcription factor.

(Modified with permission from Forrester JV, Dick AD, McMenamin PG, Roberts F, Pearlman E. The Eye: Basic Sciences in Practice. 4th ed. Edinburgh: Elsevier; 2016:110.)

• Shaham O, Menuchin Y, Farhy C, Ashery-Padan R. Pax6: a multi-level regulator of ocular development. Prog Retin Eye Res. 2012;31(5):351–376.

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.