After the lens vesicle separates from the surface ectoderm, the differentiation of the epithelial cells in the vesicle accelerates. The cells of the posterior wall expand and tend to be fusiform shaped. They protrude from the posterior wall toward the center of the lens vesicle, with their nuclei gradually migrating from the center to the front of the cells. Then, the cells gradually elongate and their nuclei move close to the cellular equator. During this process, the lumens in the lens vesicle are getting narrower and narrower, changing gradually from an empty sphere to an arc-filled or crescent-filled sphere. As the fusiform lens fiber cells reach the anterior subcapsular epithelium, the vesicle lumen disappears and a solid sphere comes into being. The nuclei in the elongated fiber cells gradually disappear and finally, the cells differentiate completely into fibers, which are referred to as the primary lens fibers. Thus, the primary lens fibers become the embryonic nucleus. Embryonic nuclear cataract is caused by the malformation of the front apices of the primary lens fibers in the sixth to the eighth week of gestation and manifests as small, sporadic white opacified dots in the central lens. It is less likely to affect visual acuity.

In the seventh week of gestation, the epithelial cells derived from the lens equatorial zone begin to differentiate, become spindle shaped, and migrate toward the central core of the lens vesicle. Their anterior pole grows toward the anterior subcapsular epithelium and their posterior pole toward the posterior capsule, meeting the lens fibers coming from the opposite direction at the posterior and anterior poles of the lens. These fibers lie tightly outside the primary lens fibers and encircle the latter layer by layer. The secondary lens fibers encircling the embryonic nucleus are also known as the fetal nucleus. If the lens is impaired in the third month of gestation, fetal nuclear cataract will occur and manifest as opacity between the anterior and posterior Y sutures, which is often combined with embryonic nuclear cataract and impacts visual acuity significantly.

The PAX6 gene is a highly conserved paired box gene, which acts as a “master control” regulator for ocular development. The products of PAX6 are DNA-binding proteins and transcription factors. PAX6 is expressed as early as in the precursor cells of the lens placode and is essential for lens placode formation [7]. PAX6 proteins are classified within a sparse group of “master” regulatory proteins, including BSAP/Pax5, Gata1, Gata2, MyoD, PU.1, Runx2, Sox9, and a few others, that work at the top of genetic networks as “molecular switches” that control cell type specification and differentiation. The PAX6 function is dosage dependent, such as haploinsufficiency. Mutation or loss of one allele in humans leads to a spectrum of eye abnormalities including lack of iris, cataract, corneal opacification, and neovascularization, as well as optic nerve hypoplasia [8]. The first notable phenotype of PAX6 deficiency was reduced size of the eye with progressively deteriorating eye morphology in mouse or rat. PAX6 regulates the expressions of various transcription factors, such as Sox2, Maf, and Prox1, which, in turn, regulates lens fiber differentiation and lens formation [9]. During the lens fiber differentiation, PAX6 ensures the differentiating cells exit from cell cycle, elongation, and expression of lens fiber-specific proteins, such as crystallins, and complete the lens formation. PAX6 can also act cooperatively with transcription factors, like Maf, Prox1, Sox2, and Six3, and exert its function via other factors like pRB and Mitf. Xia and colleagues examined the expression of PAX6 at different developmental stages of the lens in mice and found that PAX6 was expressed on embryonic day (E12.5) and E17.5 and on days 10, 20, and 60 after birth [10]. The expression of PAX6 was evenly expressed in lens epithelium. The results suggest that PAX6 is not only required for lens embryonic development but also essential for the continuing lens fiber differentiation after birth. In vitro studies also confirmed that the normal expression of the PAX6 gene was vital for the proliferation and differentiation of lens epithelial cells [11]. Furthermore, PAX6 is essential for lens fiber regeneration after cataract surgery [12].

The Maf proteins are a family of transcription factors containing the basic region of bZIP (basic region-leucine zipper). Two copies of the Maf protein or a copy of Maf protein and a copy of another related protein form a dimer, which can bind to specific DNA sequences. Members of the Maf family include L–Mafs, C–maf, V–maf, MafB, and NRL. In 1998, it was discovered for the first time that L–Maf, a member of the Maf gene family, plays a key role in lens development [5]. It affects the chick αA-crystallin expression by regulating the enhancer αCE2 [13]. Later studies discovered that C–maf and MafB of the Maf family also participate in lens development [14–16]. In addition, studies also confirmed that the missense mutation of the Maf gene can cause congenital cataract [17]. Hence, the Maf gene family directly participates in lens development and their mutations may cause cataract. However, recent studies have also shown that for lens development, only C–Maf is essential, while L–Maf and MafB appear redundant [18].