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. 2023 Nov 9;308(7):1838–1850. doi: 10.1002/ar.25345

The elusive scleral cartilages: Comparative anatomy and development in teleosts and avians

Tamara A Franz‐Odendaal 1,✉
PMCID: PMC12152821  PMID: 37943147

Abstract

The sclera of all vertebrate eyes is comprised of connective tissue, with some organisms developing cartilage within this tissue. A review of the cartilages that have been described in the vertebrate sclera and their anatomical relationships is discussed together with their potential homology. Incorrect terminology erroneously implies similarity in location, development, morphology, and evolution, which may lead some scientists to assume all cartilages in orbit are the same elements when reading the literature. Therefore, new terminology to distinguish the different types of cartilage associated with the vertebrate eye is proposed. The scleral cartilages that are likely homologous to one another and which are situated in the sclera, should be termed scleral cartilages sensu stricto, while other cartilages in the sclera should be termed ocular cartilages. Some of the cartilages also ossify, and these bones should be distinguished from the scleral ossicles. The plasticity of the scleral tissue layer and its range of morphologies from fibrous to cartilaginous connective tissue across different vertebrate lineages are also described. This review also highlights several gaps in our understanding of the vertebrate scleral cartilages, in particular.

Keywords: birds, fishes, ocular, sclera, skeleton

1. INTRODUCTION

The vertebrate eye develops as outgrowths of the diencephalon that are surrounded by the periocular mesenchyme. These outgrowths contact the surface ectoderm before differentiating into the optic cups, which are composed of an inner neural retina and an outer retinal pigmented epithelium (RPE). The surrounding mesenchyme develops into the choroid and scleral layers. The choroid layer consists of a vascular network supplying the outer retina, while the sclera is a dense fibrous layer that is continuous with the cornea. Both the sclera and the cornea are derived from neural crest cells (Creuzet et al., 2003; Kague et al., 2012). Over the course of development, the transparency between the cornea and sclera becomes distinct, resulting in a completely transparent cornea that ensures a sharp retinal image, and an opaque sclera that prevents the scattering of light and maintains image quality. In many vertebrates, cartilages develop within the scleral layer, and these elements are the focus of this review.

The sclera does not contribute to visual perception but rather provides structural support and helps maintain intraocular pressure. In many terrestrial animals that use corneal accommodation (e.g., some birds and lizards), the retinal image is stabilized by a balance of intraocular pressure and curvatures of the sclera and cornea (tab. 1 in Franz‐Odendaal, 2020; Ott, 2006; Walls, 1942). To maintain this balance, the rigidity of the sclera is essential. In contrast, other animals (e.g., bony fish, amphibians, snakes, turtles, etc.) typically use a lenticular mode of accommodation, particularly when they are in the water (tab. 1 in Franz‐Odendaal, 2020; Ott, 2006; Walls, 1942). Regardless of the mode of accommodation, the sclera must be rigid enough for the eyeball to be rotated by powerful extraocular muscles adhering to the sclera (e.g., Curtis & Miller, 1938; Franz‐Odendaal et al., 2007; Hadden et al., 2021; Murphy & Dubielzig, 1993; Nakamura & Yamaguchi, 1991; Walls, 1942).

The sclera of all vertebrates is composed of fibrous connective tissue. This layer of the eye can have different microanatomical compositions of fibers and cells. In many vertebrates (e.g., avians, most other reptiles, marsupials, etc.), some cells within this connective tissue layer differentiate into chondrocytes that secrete an abundance of collagen type II fibers, which are cross‐linked to form a cartilaginous element (e.g., Franz‐Odendaal, 2020; Franz‐Odendaal & Hall, 2006; Hall, 1981; Schwab & McMenanmin, 2005). In other vertebrates (e.g., placental mammals, and snakes), the connective tissue layer remains fibrous with no distinct cartilage, and the fibroblast cells are surrounded by a different composition of extracellular matrix fibers, such as elastic, reticular, and collagen fibers (Caprette et al., 2004; Franz‐Odendaal & Hall, 2006). When cartilage occupies parts of the sclera, the rest of the sclera is composed of fibrous connective tissue. Thus, one can think about the presence or absence of the scleral cartilage along a trajectory of connective tissue states, such that the fibrous connective tissue layer may or may not become cartilaginous in some regions of the sclera (Figure 1).

FIGURE 1.

FIGURE 1

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Diagram illustrating the differentiation pathways of connective tissues within the vertebrate sclera. Periocular mesenchyme surrounds the optic cup. The mesenchymal cells in the scleral portion then differentiate into fibroblasts and secrete extracellular matrix fibers to form a fibrous connective tissue. In some vertebrates, cells within the inner layer of the sclera further differentiate into chondroblasts and secrete collagen type II to form cartilage. The dashed vertical line represents the point of divergence amongst vertebrates, with some remaining with a fibrous sclera and others further differentiating.

For those organisms that develop scleral cartilage, the overall process of cartilage formation (chondrogenesis) is similar since it is a highly conserved and tightly regulated process in vertebrates (e.g., Creuzet et al., 2005; Hall, 2008, 2015). It starts with the reciprocal signaling between an epithelium and the mesenchymal cells destined to become the chondrocytes. Following this epithelial–mesenchymal interaction, mesenchymal cells aggregate, forming a chondrogenic condensation (Hall & Miyake, 2000). The cells within this condensation then differentiate into chondroblasts, proliferate actively, and then differentiate into chondrocytes.

The aim of this review is to clarify the anatomical relationships between the cartilages and bones of the vertebrate eye, to provide new terminology to describe them that distinguishes them from one another, and then to compare the morphology, structure, and development of the homologous scleral cartilages of teleosts and avians.

2. WHAT IS THE SCLERAL CARTILAGE? A NOTE ABOUT TERMINOLOGY

The term “scleral cartilage” has been used in the literature in different ways, which is problematic as it unnecessarily muddles discussions around homology and anatomical descriptions of fossil and extant specimens. Some authors use the word “scleral” as an adjective to describe any cartilage in the sclera as a scleral cartilage. Others, including ourselves, use the term “scleral cartilage” to describe the ring or cup‐like homologous scleral cartilage within the vertebrate eye (Edinger, 1929; Franz‐Odendaal & Hall, 2006; Walls, 1942). The additional problem with the former terminology is that if these “scleral cartilages” ossify (as in some teleosts), they are referred to as scleral ossicles or sclerotic ossicles. Again, these terms have been inconsistently used in the literature and the latter term in particular is problematic. The term scleral ossicles has been used to refer (i) to the unique scleral ossicle ring of avians and many reptiles (Figure 2), or (ii) to the ossifications that form from the cartilage ring in the teleost eye (Figure 2), or (iii) to any ossicle in the sclera (such as those described in some fishes, Mok & Liu, 2012). Furthermore, the term sclerotic ossicle is also problematic as the term “sclerotic” refers to a disease state (reviewed in Franz‐Odendaal, 2020). In summary, terminology should be carefully considered when describing or referring to the cartilages (and bones) of the vertebrate eye.

FIGURE 2.

FIGURE 2

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The scleral cartilage sensu stricto (blue) and scleral ossicles (red) in teleosts and avians form the true ocular skeleton. Red dashed line indicates the alternative shape of the scleral ossicles in teleosts to show how it can extend proximally to the cartilage element. Green dashed lines indicate other ocular cartilages and bones in teleosts. For avians, the eyeball of a chicken embryo is shown. The horse‐shoe‐shaped os opticus in adult birds is indicated in pink. The yellow shading in the embryonic chicken indicates the future location of the scleral cartilage sensu stricto. Small green arrows indicate the direction of scleral cartilage sensu stricto development in teleost and avians. The approximate position of the ora serrata is indicated with an asterisk.

Similar terminology regarding these elements can confound our understanding of identity and evolution, in some cases implying homology where none actually exists. For reasons based on their developmental origin, anatomical position and phylogenetic relationships, the scleral cartilage ring of teleosts and the scleral cartilage cup of reptiles (shaded blue in Figure 2 and Table 1) are likely homologous to one another based on Patterson's (1988) tests of conjunction (extensively discussed in Franz‐Odendaal, 2011, 2020). In contrast, other cartilages and ossicles (Table 1 highlighted in green), such as Di Dario's ossicle, are not likely homologous, as will be discussed in more detail below. Since homology may be assumed based on nomenclature, it is important to utilize distinct terminology when referring to the cartilages and bones of the sclera. We propose here that the homologous teleost cartilage ring (or partial ring) and the reptilian cup‐like cartilages of the sclera (Table 1) should be referred to as true scleral cartilages or scleral cartilages sensu stricto. The other smaller and often inconsistent cartilages within the sclera should be termed ocular cartilages (Table 1). Following this notation, in the case of teleosts where cartilages in the orbit may ossify, use of the term scleral ossicles should only be used when describing those ossicles that form directly from the scleral cartilage sensu stricto element and should not be used to describe other ossicles or bones in the eye. These latter ossicles or bones should be termed ocular ossicles. In the case of reptiles (including avians), the ring of overlapping scleral ossicles (Figure 2) does not have a cartilage phase and their terminology is unambiguous; they should be called intramembranous scleral ossicles (Franz‐Odendaal, 2011; Franz‐Odendaal & Vickaryous, 2006). The scleral cartilage sensu stricto and the scleral ossicles collectively make up the true ocular skeleton (Figure 2 and Table 1), one that has a long evolutionary history (e.g., Edinger, 1929; Franz‐Odendaal, 2020; Franz‐Odendaal & Hall, 2006; Gugg, 1938; Lima et al., 2009; Mok & Liu, 2012; Nakamura & Yamaguchi, 1991; Walls, 1942; Yamashita et al., 2015). This terminology is summarized in Figure 3. The focus of this review is to describe the morphology, structural characteristics and development of the scleral cartilages sensu stricto; however, a discussion of the scleral ossicles and the other ocular cartilages and bones is warranted given the issues with terminology highlighted above.

TABLE 1.

Cartilages and ossicles of the vertebrate eye.

New terminology Current terminology Anatomical location Organism Size N Shape Ossifies yes or no References
Scleral cartilage sensu stricto Scleral cartilage Extends from back of eyeball up to the scleral–corneal limbus All avians, most reptiles a Medium to large 1 Cup‐like No Lemmrich (1931), Curtis and Miller (1938), Franz‐Odendaal and Vickaryous (2006), Lima et al. (2009), Franz‐Odendaal (2011)
Scleral cartilage Located in the widest part of eyeball (approx. close to the equator of the eye) Almost all teleosts b Small to large 1 Ring‐like or partial ring May ossify in regions in some teleosts c or remain unossified in adults Franz‐Odendaal et al. (2007), Franz‐Odendaal (2008), Nakamura and Yamaguchi (1991), Mok and Liu (2012)
Intramembranous scleral ossicles Scleral ossicles Ring of bones within the scleral–corneal limbus Avians and reptiles Small 13–16 Flat rhomboid Yes (no cartilage phase) Edinger (1929), Walls (1942), Franz‐Odendaal and Hall (2006), Franz‐Odendaal (2011), etc.
Ocular cartilages Scleral cartilage Ossified cartilage in posterior part of eyeball Teleost: Denticeps clupeoides Small 1 Irregular circular Yes, ossifies as Di Dario's ossicle Kubicek et al. (2022)
Scleral cartilage Cartilage in lower half of the orbit Hyphessobrycon species Small 1 Rhomboid flat No Benjamin (1990)
Ocular ossicles Scleral ossicles Adjacent to scleral ossicles, no cartilage phase Teleosts: Elops machnata, Albula glossodonta; Megalops cyprinoides Small 1–2 Irregular Yes Mok and Liu (2012)
os opticus or Gemminger's ossicle os opticus or Gemminger's ossicle Situated at the base of the scleral cartilage sensu stricto and surrounds the optic nerve Avians: 219 species from 35 families Small 1 Horse‐shoe shaped Yes, ossifies from the scleral cartilage sensu stricto Gemminger (1853), Tiemeier (1950), Franz‐Odendaal and Vickaryous (2006)
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Note: New terminology proposes that the elements highlighted in blue should be referred to as scleral cartilages sensu stricto, elements in red as scleral ossicles, elements in green as ocular cartilages. The only element with an unchanged name is the os opticus. Refer also to Figures 2 and 3.

Abbreviation: N, number of elements.

a

See Franz‐Odendaal (2020) for reptiles that have secondarily lost the scleral cartilage sensu stricto element.

b

Benjamin (1990) reports two species that lack scleral cartilage, but these need to be re‐examined. See text for details.

c

May be fully ossified in some adult teleosts (see Franz‐Odendaal, 2008). If ossified, should be termed scleral ossicles Also Franz‐Odendaal et al. (2007) describes an usual mode of ossification in some teleosts. Importantly these elements are not homologous to the intramembranous scleral ossicles of avians and other reptiles (see Franz‐Odendaal, 2011, 2020).

FIGURE 3.

FIGURE 3

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A graphic illustrating the proposed terminology for the cartilages and bones of the vertebrate eye. The ocular cartilages and bones (upper dark gray box) are distinct from the scleral cartilage sensu stricto (green boxes), the intramembranous scleral ossicles of avians (light orange box), and the endochondral scleral ossicles of teleosts (light gray box) as described in the text. Only the sensu stricto elements are homologous to one another. Periskeletal ossification has been reported as the mode of ossification of the scleral ossicles in zebrafish (see text)

3. THE OCULAR CARTILAGES AND OSSICLES

Apart from the scleral cartilage sensu stricto element, three additional cartilages and ossicles are reported in some teleost species (Table 1). These skeletal elements are situated above or below the scleral cartilage sensu stricto (e.g., in Elops machnata, Albula glossodonta, Denticeps clupeoides, Megalops cyprinoides, Table 1). Three of these species (Elops sp. Albula sp., Megalops sp.) were determined by Franz‐Odendaal (2008) to have completely ossified scleral cartilage sensu stricto rings or two large endochondral scleral ossicles. Therefore, the ossicles identified by Mok and Liu (2012) cannot be homologous to the scleral ossicles and should be termed ocular ossicles. Similarly, a cartilage in the posterior of the eye in some teleosts, which ossifies into Di Dario's ossicle, was noted by Kubicek et al. (2022). This element can also not be homologous to the scleral cartilage sensu stricto (also see Franz‐Odendaal, 2020), since this species also has endochondral scleral ossicles joined by the scleral cartilage sensu stricto elements in the eye. Notably, the medial rectus muscle inserts on the medial face of Di Dario's ossicle. It is not known whether these additional ocular bones have cartilage precursors or if these are sesamoid bones (Hall, 2015) that have formed within tendons or muscles. Finally, a rhomboid cartilage was identified by Benjamin (1990) in the lower half of the orbit in Hyphessobrycon fishes. This element may, on the one hand, be a miniature scleral cartilage sensu stricto since no other scleral cartilage element was reported by the author in this species. However, these fish are Characidae (Characiformes), and belong to the same family as Astyanax mexicanus and Cheirodon pisciculus, both of which have almost completely ossified scleral cartilage rings (Franz‐Odendaal, 2008). Thus it is possible that the Hyphessobrycon species (Characiformes: Characidae) examined by Benjamin did not have a scleral cartilage sensu stricto element (as reported) because it was completely ossified (i.e., it had endochondral scleral ossicles). It is unclear from the image in Benjamin (1990) whether the ring illustrated above the rhomboid cartilage element in this study is ossified, as it is unlabeled, but this looks like it could be the scleral cartilage sensu stricto that has ossified. Furthermore, an examination of five genera from this family (Characiformes) did not reveal any that lack scleral cartilage (Franz‐Odendaal, 2008). Thus, it is most likely that the rhomboid cartilage element identified by Benjamin (1990) in Hyphessobrycon is indeed an extraocular or an ocular cartilage. Benjamin (1990) further reports two species that lack scleral cartilages altogether—Corydoras metae (Callichthyidae, Siluriformes) and Clarias batrachus (Clariidae, Siluriformes). Thus, Benjamin's (1990) study is the only study reporting a lack of scleral cartilage in any bony fishes; their other studies (e.g., Benjamin & Ralphs, 1991) report the presence of scleral cartilage in 12 species of teleosts and align with the findings in Franz‐Odendaal (2008). The absence of the scleral cartilage in C. metae, C. batrachus, and Hyphessobrycon sp. needs to be re‐examined with particular attention to the age of specimens before a definitive assessment of homology can be made. It would be incorrect to record the species as lacking scleral cartilage sensu stricto if this element is present in juveniles (i.e., in the cases where it later ossifies into a scleral ossicle ring or into separate ossicles). Thus, in summary, the scleral cartilage sensu stricto ring in teleosts (which may present as two elements joined by ossified regions if the cartilage ossifies, or may appear absent if the entire ring ossifies, Franz‐Odendaal, 2020), and the scleral cartilage sensu stricto cup of avians, while homologous to one another, are likely not homologous to the other identified ocular cartilages of the sclera that have been reported to date (in Table 1 and Figure 3).

4. DISTRIBUTION OF THE SCLERAL CARTILAGE SENSU STRICTO ACROSS VERTEBRATES

The scleral cartilage sensu stricto is present in many adult vertebrates (e.g., avians, teleosts, and chondrichthyes), however, it can sometimes be present only during development (e.g., in some amphibians) (Caprette et al., 2004; Eyal‐Giladi & Zinberg, 1964; Franz‐Odendaal & Hall, 2006; Franz‐Odendaal & Vickaryous, 2006; Pokorny et al., 2013; Walls, 1942). This element is completely absent in placental mammals and marsupials, and has been secondarily lost over evolutionary time in some reptile lineages (e.g., in snakes, etc.) (Franz‐Odendaal, 2020). In some vertebrates, this element may ossify (e.g., in many teleosts, Benjamin, 1990; Edinger, 1929; Franz‐Odendaal, 2008; Walls, 1942), or it may contain calcified regions within the cartilage known as tesserae (as in some sharks, Pilgrim & Franz‐Odendaal, 2009). The scleral cartilage sensu stricto does not ossify in extant reptiles, including all birds. The gross morphology, microanatomical structural characteristics, and the development of the avian and teleost homologous scleral cartilages sensu stricto are discussed below in detail.

5. THE SCLERAL CARTILAGE SENSU STRICTO OF TELEOSTS

5.1. Morphology

All teleost fish have a scleral cartilage ring in their eye at some stage of development or as adults (e.g., Benjamin, 1990; Franz‐Odendaal & Hall, 2006; Walls, 1942; see Table 1). This ring is typically present at the widest part of the eyeball, slightly anterior to the equator of the eye (i.e., closer to the cornea, Figure 2). This ring of cartilage can be quite deep or very narrow, depending on the species (Franz‐Odendaal et al., 2007; Zinck & Franz‐Odendaal, 2022). A cup‐like scleral cartilage is also noted in the blind cave morph of A. mexicanus (Dufton et al., 2012; O'Quin et al., 2015), which is in stark contrast to the sighted morph of this species that has two cartilage elements joined by two ossified elements in adults (Franz‐Odendaal et al., 2007).

The scleral cartilage sensu stricto of teleost fishes may, therefore, present as a replacement (i.e., temporary) cartilage that later ossifies or as a permanent cartilage. In teleosts with a replacement cartilage ring, the perichondral cells of the larval scleral cartilage ring are triggered (by an unknown mechanism) to initiate ossification rostrally and caudally forming one or two scleral ossicles (Franz‐Odendaal et al., 2007; Franz‐Odendaal & Vickaryous, 2006; Nakamura & Yamaguchi, 1991; Walls, 1942). This ossification may completely replace the cartilage ring (as in swordfish) or may only partially replace the cartilage ring (as in zebrafish) (reviewed in Franz‐Odendaal, 2020). Typically, two ossicles form in the eye, one rostrally (anterior) and one caudally (posterior). The anterior ossicle serves as a point for the insertion of the dorsal obliquus and the dorsal rectus eye muscles, whereas the ventral obliquus, ventral rectus, and lateral rectus insert on the posterior scleral ossicle (Walls, 1942). The presence or absence of ossification of the scleral cartilage in teleosts has been described phylogenetically in other studies (e.g., Franz‐Odendaal, 2008; Franz‐Odendaal & Hall, 2006; Nakamura & Yamaguchi, 1991) and may relate to the speed of swimming, depth changes while swimming and/or perhaps eye rotation. Teleosts that are benthic and slow‐moving typically lack scleral cartilage ossification; however, not all teleosts that lack scleral ossicles are benthic (Franz‐Odendaal, 2008). It is well known that muscle activity triggers ossification in vertebrates (e.g., Hall, 2015; Nowlan et al., 2008); however, it is unclear if the ossification of the scleral cartilage observed in extant teleosts is a response to muscle activity or the response to an ancient conserved mechanism preprogrammed within the cartilage element. For example, in some blind cavefish (e.g., A. mexicanus), the scleral cartilage cup ossifies (O'Quin et al., 2015) despite the eyeball position deep within the head and surrounded by adipose tissue, presumably without muscle triggers for ossification. Small, thin extraocular muscles have been reported in the cave morph of A. mexicanus (Yamamoto, 2016); however, it is unclear when these are present or if they degenerate with increasing age, similar to the optic nerve (Wilkens, 1988, 2010).

A unique ossification mode of the scleral cartilage has been documented in zebrafish. Here, a small specialized perichondrium extends a distance from the ends of the scleral cartilage element; this perichondrial extension is what later ossifies (Franz‐Odendaal et al., 2007). Resorption pits are visible at the ends of the scleral cartilage element closest to this extension, indicating that this is the site of cartilage resorption. This ossification mode is termed unilateral periskeletal ossification (Franz‐Odendaal et al., 2007). Once initiated, the medial growth of the scleral ossicle (toward the posterior of the eyeball) appears to be independent of the scleral cartilage element since, in some fish, the ossicle width/depth will closely match that of the scleral cartilage (e.g., Mexican tetra, A. mexicanus), whereas in other fish, the growth of the ossicles can extend far deeper than the scleral cartilage element (as in zebrafish Danio rerio) (Franz‐Odendaal et al., 2007). It is not known if the scleral cartilage sensu stricto of other teleosts follows this periskeletal ossification mode.

5.2. Structural characteristics

The structural characteristics of the scleral cartilage of teleosts were documented as a special case of cartilage by Benjamin and colleagues (Benjamin, 1990; Benjamin & Ralphs, 1991) because its cell‐rich nature is unlike typical hyaline cartilage, which contains an abundant matrix with fewer cells. Benjamin (1990) further noted that cell‐rich hyaline cartilage likely has different biomechanical properties than typical hyaline cartilage. Some teleosts have distinct peripheral cell‐free matrix zones adjacent to a cell‐rich core (e.g., Cichlasoma nigrofasciatum), while in others this distinction is less apparent (e.g., Tanichthys albonubes, D. rerio, A. mexicanus) (Benjamin, 1990; Zinck & Franz‐Odendaal, 2022) (Figure 4a). The four species mentioned above all have scleral ossicles (Franz‐Odendaal, 2008). A more extensive examination of this apparent structural difference of the scleral cartilage sensu stricto is warranted since it does not appear to relate to whether the cartilage ossifies (i.e., is partially or fully replaced by bone). The scleral cartilage sensu stricto contains collagen type II, as is typical for other hyaline cartilages in avians and mammals (Benjamin, 1990; Mayne & von der Mark, 1983). In addition, chondroitin sulfate is present throughout the matrix of the scleral cartilage element, while keratan sulfate is often present pericellularly (Benjamin & Ralphs, 1991). This distribution is similar to that of hyaline cartilage.

FIGURE 4.

FIGURE 4

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Histological sections of the scleral cartilage sensu stricto of avians and teleosts. Sections are stained with Hall Brunt's Quadruple stain and schematics show the orientation of the section. (a) A single row of chondrocytes is present within the scleral cartilage sensu stricto (sc) in zebrafish 8.25 mm standard length larval fish. (b) The thick scleral cartilage sensu stricto (sc) of the chicken embryonic eye, Hamburger and Hamilton (1951) stage HH35.5–36. The zebrafish scleral cartilage element (a) has a cell‐free peripheral area (arrow in a), unlike the chicken embryonic scleral cartilage tissue. f, fibrous sclera; sc, scleral cartilage; RPE, retinal pigmented epithelium. Scale bars are 15 μm in a) and 50 μm in b).

5.3. Development

Only a handful of studies have examined the development of the scleral cartilage sensu stricto of teleosts. A recent comparative study of scleral cartilage development between zebrafish (D. rerio) and the Mexican tetra (A. mexicanus) (Zinck & Franz‐Odendaal, 2022) showed that the cartilage element is not present in either species at 10 days post fertilization (dpf). By 15 dpf, however, scleral cartilage is apparent in the sighted tetra morph and zebrafish but not in the cave tetra morph. By 20 dpf, some cavefish had developed scleral cartilage. Furthermore, the growth rate of the scleral cartilage is faster in zebrafish and cavefish compared to sighted tetras. The scleral cartilage first appears near the ora serrata, and thus it is likely that induction of the cartilage commences in this region (Figure 2, asterisk). The inductive tissue is unknown at present. When it first forms, the cartilage ring is nonuniform in depth, however, it appears to attain uniformity once the growth rate slows down (Zinck & Franz‐Odendaal, 2022). This ability to attain uniformity could be indicative of a controlling mechanism that aligns the depth such that the cartilage is uniform in adults. Only one study has examined the genetic basis of scleral cartilage ossification (O'Quin et al., 2015), and this was conducted in the Mexican tetra, A. mexicanus. These researchers identified that multiple loci responsible for lens degeneration may generate a genetic threshold for scleral ossicle absence. They further found that the scleral ossicles have been reduced convergently amongst several cavefish populations. How these findings translate to other teleosts is currently unknown. Interestingly, the chondrocytes of the scleral cartilage are also significantly larger in the cave morph compared to the sighted morph of A. mexicanus, but not larger than the chondrocytes in other cranial cartilages (Zinck & Franz‐Odendaal, 2022). Why the scleral cartilage cup of the blind cavefish has larger chondrocytes than the cartilage ring element in the sighted morph is unclear. It is possible that the scleral cartilage of the sighted morph is in an active state of growth and the cells are proliferating compared to a slowing down of chondrogenesis (if any) in the blind cavefish in which the eye is no longer growing. Differential regulation of chondrocyte proliferation and hypertrophy may be the result of recently acquired gene expression differences between the sighted and cave morphs (O'Quin et al., 2015).

6. THE SCLERAL CARTILAGE SENSU STRICTO OF AVIANS

6.1. Morphology

In contrast to teleosts, the scleral cartilage sensu stricto of all avian eyes is a permanent cartilage (Figures 2 and 4b). It is situated adjacent to the retina and is typically cup‐like in shape. Avian eyes have different shapes (e.g., tubular eyes of owls compared to the round eyeballs of chickens) and these shapes dictate the scleral cartilage shape and size, as well as the shape of the scleral ossicles that form later (e.g., Franz‐Odendaal & Krings, 2019). Scleral ossicles in avians (and other reptiles), are flat bones that are situated within the sclera (at the scleral–corneal limbus) and that form independently of the scleral cartilage (Franz‐Odendaal & Vickaryous, 2006). They are also intramembranously ossifying bones, unlike in teleosts. When scleral ossicles are large, as in owls, the scleral cartilage is restricted to the back of the eyeball into a shallow cup‐shape (Franz‐Odendaal & Krings, 2019; also see fig. 2 in Franz‐Odendaal, 2020) rather than the deep cup‐shape morphology that is typically observed in most bird species (e.g., chickens, Figure 2). Situated within the scleral cartilage sensu stricto element of birds at the site where the optic nerve enters the eye is an ossified, horse‐shoe‐shaped element, the os opticus (or Gemminger's ossicle). The terminology for this element should remain unchanged as it is a distinct endochondral bone that is derived from the scleral cartilage sensu stricto element (Table 1 and Figure 2).

6.2. Structural characteristics

The scleral cartilage of chicken embryos is hyaline in nature, with large chondrocytes and moderate amounts of matrix (Figure 4b). The cartilage is situated in the inner portion of the sclera closest to the retina, whereas the outer portion of the sclera is fibrous. The cartilaginous layer consists of chondrocytes, collagen type II, and large amounts of aggrecan, decorin, tenascin C, and a meshwork of collagen type II, IX, and X fibrils (Crawley et al., 1995; Hammer & Franz‐Odendaal, 2018; Heinegård & Oldberg, 1989; Matthews & Rada, 1993; Pearson & Sasse, 1992). In chickens, the outer fibrous portion of the sclera is itself composed of two layers, a thinner inner portion and a thicker outer portion containing fibroblasts, collagen type I, small proteoglycans like decorin and biglycan as well as larger proteoglycans like aggrecan and tenascin C (Crawley et al., 1995; Hammer & Franz‐Odendaal, 2018; Kusakari et al., 2001; Rada et al., 1991; Rada et al., 1994).

Research in chicken embryos has shown an inverse relationship between the thickness of the scleral cartilage and the thickness of the scleral fibrous layer. When myopia, a condition in which the eye is too long for the focal length of the cornea and lens, is induced in chicken embryos, the fibrous layer thins while the cartilaginous layer thickens (Gottlieb et al., 1990). Matrix metalloproteinases (also known as matrixins) are proteins that degrade the extracellular matrix and are typically activated when an N‐terminal propeptide is cleaved. These proteins have been studied in the context of myopia. Myopia results in increased levels of matrix‐metalloproteinase‐2 (MMP‐2) and reduced levels of tissue inhibitors of matrix metalloproteinase‐2 (TIMP‐2) in the fibrous sclera as well as elevated levels of aggrecan (Rada et al., 1991; Rada et al. 1999). The substrates for MMP‐2 include aggrecan, gelatin, fibrillar and non‐fibrillar collagens, and fibronectin (Aimes & Quigley, 1995). As such, the elevation in both aggrecan and MMP2 in myopic eyes makes sense. Furthermore, pro‐MMP‐2 must be extracellularly activated by membrane‐type MMP‐1 and TIMP‐2 (Strongin et al., 1995; Will et al., 1996). Transforming growth factor‐beta (TGFβ) is known to influence collagen, proteoglycan, and MMP‐2 production in the extracellular matrix (Overall et al., 1989) and is, therefore, a good candidate for controlling sclera remodeling in myopic eyes (Schippert et al., 2006). TGFβ2 is significantly upregulated in the cartilaginous layer following treatment with a positive (convex) lens (Schippert et al., 2006), suggesting that there is a feedback loop within the eye between visual accommodation and the scleral layers. Furthermore, intravitreal injection of muscular antagonists (including atropine) into chicken embryonic eyes inhibits cell proliferation and extracellular matrix production within the cartilaginous layer of the sclera but not the fibrous layer (Gallego et al., 2012; Lind et al., 1998). Interestingly, experimentally induced visual deprivation has also been shown to transform the fibrous sclera into a cartilaginous sclera in chickens (Kusakari et al., 2001). These experiments highlight the plasticity of the scleral mesenchyme to change from fibrous to cartilaginous (discussed later).

6.3. Development

Cartilage development involves reciprocal epithelial–mesenchymal interactions in all vertebrates (Hall, 1981). Generally, these mesenchymal cells are of mesodermal or neural crest origin, while the epithelial layer is usually derived from ectoderm or endoderm (Couly et al., 2002; Crump et al., 2004; Hall, 1981). In developing avian limb buds, where cartilage development has been most studied, mesenchymal cell condensations destined to become cartilage initially express transcription factors such as SOX9 and CART1 (Alx1) (Wright et al., 1995; Zhao et al., 1994) and later express other transcription factors (namely, SOX5 and SOX6), as well as matrix molecules collagen type II and aggrecan (Lefebvre et al., 1998; Swalla et al., 1988). The cartilage of the limbs are example of replacement cartilage (as they are ultimately replaced by bone), unlike permanent cartilage, such as the scleral cartilage of the reptilian eye, which remains cartilaginous throughout life.

Thompson et al. (2010) showed the differential expression pattern of various markers for cartilage within the developing scleral cartilage in chicken embryos, starting with CART 1, the earliest marker of precommitted cartilage expressed at HH16 (E2.5), followed by expression of SOX9, and aggrecan, and leading to differentiated cartilage at HH34 (E8). This expression pattern is summarized in Figure 5. Importantly, the expression of these markers is located closest to the inner part of the sclera, immediately adjacent to the RPE, which is also the location where the scleral cartilage later forms. Once formed, other extracellular matrix molecules are strongly expressed within the scleral cartilage at HH 37 (E11), including tenascin C, decorin, and procollagen 1 (Hammer & Franz‐Odendaal, 2018). Furthermore, their expression data corroborates data by Coulombre and Coulombre (1958), which shows that the cartilage development follows an anterior (closest to the cornea) to posterior (closest to optic nerve) direction (Figure 2, green arrow). Further supporting this directional information is the finding that the transcription factor PITX2 is required for the scleral fate and that PITX2 is first expressed in the anterior eye chamber (Evans & Gage, 2005; Gage & Zacharias, 2009; Kumar & Duester, 2010).

FIGURE 5.

FIGURE 5

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A summary of scleral cartilage gene expression in avian embryos from Thompson et al. (2010). The gradient shading in the rectangles indicates the first expression (pale shading) to the strongest presence (dark shading) of the gene.

In chicken embryos, in vitro and in vivo studies have further suggested that the RPE may induce scleral cartilage development (Newsome, 1972; Stewart & McCallion, 1975; Thompson et al., 2010). The experimental manipulations conducted by Thompson et al. (2010), were conducted on enucleated embryos in which the optic cup was removed or the RPE regrafted or replaced by a soaked bead. These experiments showed a loss of CART1, SOX9, and AGGRECAN after removal of the optic cup, which led to the conclusion that the optic cup is necessary for scleral cartilage induction. Furthermore, by regrafting the RPE into cranial mesenchyme, cartilage was induced, leading these authors to conclude that the RPE is necessary for cartilage induction. It is possible that some mesenchymal cells were carried with the RPE graft, which the authors note, suggesting that these cells could carry the signal for cartilage induction (Thompson et al., 2010). Furthermore, these grafting experiments were only conducted at one developmental stage (embryonic day 3), after the first expression of CART1 and several days before definitive cartilage is present (Figure 5). Additional research is needed to further understand the timing and mechanism of scleral cartilage induction in avian embryos.

7. PLASTICITY OF THE SCLERAL TISSUE

When one considers the ability of the scleral mesenchyme of myopic chicken embryos to switch between cartilaginous and fibrous states, together with data from the blind cavefish A. mexicanus, which has a cartilaginous sclera, it suggests that the scleral mesenchyme is plastic and can respond to both muscular and visual cues. Plasticity within the vertebrate eye has been demonstrated in the retinal layers of cichlid fish after long‐term visual deprivation (Wagner & Kroeger, 2015). Thus, the lack of visual cues may lead to the development of a permanent cartilage rather than a replacement cartilage, which will later partially or fully ossify. Indeed, in reptiles, the bulk of eye development (including sclera development) occurs in ovo, unlike in teleosts when it occurs posthatching. Furthermore, this ability to switch fates is also retained in placental mammals, as cartilage nodules have been noted in the human sclera (Seko et al., 2008). The ability of the scleral mesenchyme to remodel from a fibrous connective tissue to a cartilaginous one (during development) and a reversal of this remodeling (in myopic eyes) should be taken into account when evaluating the evolution of the scleral cartilage sensu stricto elements over vertebrate phylogeny. The cartilaginous sclera is considered a derived condition from an ancestral fibrous scleral capsule (see Franz‐Odendaal, 2011; Franz‐Odendaal & Hall, 2006).

8. A NOTE ABOUT FUNCTION

In all vertebrates, the scleral cartilage sensu stricto provides rigidity for the insertion of muscles required for eye rotation and to counter the traction force of the extraocular muscles (Franz‐Odendaal & Vickaryous, 2006). Additional functions may relate to visual accommodation, however, the requirements for and the mechanisms of visual accommodation differ greatly between avians and teleosts (reviewed in Franz‐Odendaal, 2020). In avians, intraocular pressure is altered during corneal accommodation and the scleral cartilage sensu stricto is thought to prevent image distortion during this visual accommodation process. In teleosts, however, intraocular pressure does not change during visual accommodation. However, external water pressures are higher in deeper benthic environments, therefore, more mechanical support in the form of deeper cartilage rings is likely needed. A detailed examination of the distribution of deep versus narrow scleral cartilage rings in teleosts has not been conducted to date.

9. SUMMARY

This comparative review highlights the similarities and differences between the scleral tissue of avians and teloests, while also noting several gaps in our knowledge. These include the need to further understand (i) the trigger(s) for ossification of the teleost scleral cartilage sensu stricto, (ii) the ability of the scleral tissue to remodel and whether this is linked to visual deprivation as suggested by data from the blind cavefish, chickens and humans, (iii) the variation in the scleral cartilage sensu stricto gross morphological and microanatomical structure amongst teleosts, and (iv) the induction of the scleral cartilage sensu stricto in both chicken embryos and larval fish. This review also highlights the importance of nomenclature and its implications for inferred homology. The review proposes the use of the term scleral cartilage sensu stricto for the elements with homology across vertebrates, the term scleral ossicles for those elements that form the other component of the true ocular skeleton, and the use of the term ocular cartilages and ocular ossicles for those elements without demonstrated homology and which are not part of the true ocular skeleton. Much research is still required to fully understand the complexities of the development and evolution of the cartilages of the sclera across vertebrates to fully understand vertebrate eye evolution, development, and anatomy.

AUTHOR CONTRIBUTIONS

Tamara A. Franz‐Odendaal: Conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; resources; software; visualization; writing – original draft; writing – review and editing.

ACKNOWLEDGMENTS

This research was funded by a Natural Sciences and Engineering Research Council (Canada) grant.

Franz‐Odendaal, T. A. (2025). The elusive scleral cartilages: Comparative anatomy and development in teleosts and avians. The Anatomical Record, 308(7), 1838–1850. 10.1002/ar.25345

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