Role of Melanin Pigment in Retina and Inner Ear

Abstract

Melanin pigment is normally present in the outermost layer of the retina of the eye, the inner ear adjacent to capillaries in stria vascularis near hair cells, and vestibular organs. Significant reduction in melanin pigment in mammals is associated with embryonic miswiring and disruption of visual and auditory functions. The consequences for the visual system include abnormal development of the retina and misrouting of optic pathways into the brain impairing visual acuity, eye movement, and stereovision. Lack of melanin pigment in the inner ear is associated with greater susceptibility to noise damage and poorer localization of sound in space.

1. Introduction

The organization of the visual system varies among mammals. Most primates display well-defined retinal foveae, foveal avascular zone, and large numbers of uncrossed optic fibers at the optic chiasm. Mammals with laterally placed eyes, for example, guinea pig, rat, mouse, have little temporal retina producing few uncrossed fibers at optic chiasm. Cats and more so primates with forward-facing eyes have significant temporal retina, with nearly half of optic fibers remaining uncrossed at the chiasm of some primates. Mammals vary in proportion of optic nerve fibers that cross at the chiasm, embryonic development and optic projections terminating in vision centers from suprachiasmatic nuclei to midbrain, to geniculate nuclei, to visual cortex.

Most albino human beings and albino cats lacking retinal pigment have observable nystagmus and many exhibit strabismus. The optic chiasm of albino mammals including human beings and cats shows that almost all retinal ganglion cells cross at the optic chiasm with few uncrossed optic fibers. This misrouting has dramatic effects on organization of the visual system.

In 1965, C.L. Sheridan noticed that retinal ganglion cells originating in temporal retina of albino rats did not function well, hypothesizing that albino rats have fewer uncrossed, non-decussating optic fibers [1]. R.D. Lund anatomically verified that albino rats have fewer non-decussating optic fibers compared to pigmented rats [2]. For several years the abnormality of reduced non-decussating optic fibers at the optic chiasm in albinos was thought to be limited to rats and rabbits [3]. Guillery [4] reported atypical visual system organization in Siamese cats, but the association with albinism was not identified.

In 1971, Creel initially published the connection between Siamese cats and albinism, and hypothesis that reduced non-decussating optic fibers likely is a “highly general transspecies phenomenon in albino mammals” [5, 6]. Siamese cats, Himalayan mice, rats, and rabbits express a mutation that is a temperature-sensitive pigmentation defect, that is, allowing pigment only on the cold parts of the body. Their retinae lack pigment.

The studies of Siamese cat showed that a single recording site over each visual cortical area reflected differences between pigmented and albino cats [5]. Hence, scalp-recorded visually evoked potentials might detect optic misrouting in human albinos. Testing human albinos using scalp-recorded visually evoked potentials revealed human albinos have reduced non-decussating optic fibers [6, 7]. Animal studies reported that all albino mammals with oculocutaneous, or only ocular albinism, demonstrate reduced uncrossed optic projections [8, 9, 10]. Visual system abnormalities in albino mammals include fewer photoreceptors, foveal/area centralis hypoplasia, misrouting of the temporal retinal ganglion cells, variation of geniculate terminations, vascular intrusion into foveal area, abnormal cortical projections, and fewer cones in macular area [11, 12, 13, 14, 15, 16, 17].

The animal model close to organization of primate visual system studied the most is the albino cat. Albino cats have observable nystagmus, and many have strabismus. Figure 1 pictures the optic chiasm of an OCA1 albino cat showing almost all retinal ganglion cells (RGCs) cross at the chiasm. The number of binocular cells is reduced in visual cortical areas 17, 18, and 19 in Siamese cats and albino cats impairing stereovision [19, 20, 21].

Figure 1.

Dark-field autoradiograph of coronal section through the optic chiasm of a Type 1 albino cat after injection of tritiated leucine into right eye showing difference between contralateral and ipsilateral RGC projections. Almost all RGCs cross at the optic chiasm. Arrows point to projections to suprachiasmatic nuclei. Scale bar 1 mm. From Creel et al. [18].

Phylogenetically older connections are less abnormal in albino mammals as seen in Figure 1 showing bilateral suprachiasmatic projections appear to be unaffected [18]. Optic projections near chiasm projecting into hypothalamus antecede vertebrates, occurring in early chordates. Chordates have retinal pigment matching vertebrates [22]. Melanopsin retinal ganglion cells are completely crossed or bilaterally projected into suprachiasmatic nuclei above the optic chiasm [23, 24]. These projections are not affected by albinism. The crossed/uncrossed proportion of optic neurons to the suprachiasmatic nuclei in albino cats is like the proportion stated for pigmented cats [25]. The earlier appearing melanopsin pathway is not affected.

Abnormalities associated with hypopigmented retinae vary between species. Most human albinos have poorly formed foveae and little or no vascular sparing of central foveal area of retina [12, 26]. Visually evoked potential studies and functional magnetic resonance imaging reflect the preponderance of crossed optic fibers at the chiasm [15]. Few retinal ganglion cells originating temporal side of fovea in pigmented human beings cross at the optic chiasm. In albino mammals most retinal ganglion cells originating in temporal retina cross at the optic chiasm. Figure 2 shows approximate differences between the optic chiasm of ocularly pigmented and albino human beings.

Figure 2.

Schematic of approximate distribution of crossed and uncrossed optic fibers in human beings. From Creel, webvision.med.utah.edu (2014).

Many possibilities are suggested for controlling embryonic retinal ganglion cells coursing through the chiasm. Some conclusions are likely to be correct within the model studied, but not a solution for optic misrouting seen throughout albino mammals. Each species varies. As an example, significant differences between mouse and human embryogenesis specific to chiasm formation are described [27]. Temporal timing of axon arrival at the optic chiasm and path through the chiasm are different between man and mouse. The development of contralateral followed by ipsilateral optic projections is sequential. There are no absolutes. Variable expression is seen even in littermate animal models [9]. Additionally, exceptions are reported [28, 29].

Due to millions of years of divergent evolution, the micro mechanisms of axon guidance underlying optic neuron decussation and target fate are likely idiosyncratic for each species. Pax2, Pax6, SOX2, and SOX21 seem to participate in development of the visual system. Several conserved loci including ROBO and PAX2/PAX 6 affect guidance in mammals including humans [14, 30, 31, 32, 33].

Additionally, intra-genome communication is probably taking place. Visual embryogenesis is possibly affected by contributions from noncoding DNA and conserved noncoding portions of the genome. Noncoding DNA probably modifies expression [32, 33]. Variance within species appears to originate more in noncoding space [34].

Melanin is present in vertebrates and seen in early chordates. Melanin pigment is prevalent in mammalian embryonic development. Melanin pigment’s function in the eye is different than in other parts of the body. Melanin pigment is present with melanocytes that are mostly active during early vertebrate embryogenesis. The melanin pigment chemical pathway initiated with tyrosine is expressed similarly from drosophila to primates. The sequence leading to eye formation in the fly is recapitulated in the developing human eye [35, 36]. Phylogeny is recapitulated in the embryonic development of the mammalian visual system.

1.1 Human pigmented vs albino visual system

Figure 3 shows OCT (optical coherence tomography) of the foveal area of a pigmented person (A) and an albino (B). In pigmented retina, the red nerve fiber layer does not cross the fovea. In most human albinos the nerve fiber layer (B) passes over fovea. Poor foveal development and variability among albino foveae are likely due to amount of ocular pigment and genetic background [37]. Albino human beings manifest a reduction in cone density in the central retina [13]. Ocularly pigmented primates are the only mammals with developed foveae. In most mammals with albinism, the retinal macular area is underdeveloped [38, 39].

Figure 3.

Ocular coherence tomography (OCT) through the fovea of a normally pigmented (A) and albino (B) human being. Note the absence of foveal pit with the nerve fiber layer (red) continuing over foveal area in albino retina. From Creel, webvision.med.utah.edu (2014).

In humans with pigmented retinae, retinal blood vessels spare the foveal area. In albino human retinae, blood vessels intrude into foveal area. Figure 4 compares the central vascular distribution in human pigmented and albino retinae. Pigmented humans exhibit an avascular zone surrounding the fovea. Albinos do not.

Figure 4.

Angiogram of pigmented human ocular fundus (A) showing vascular sparing of foveal area compared to albino (B) with vascular intrusion into vascular area. From Creel, webvision.med.utah.edu (2014).

1.2 Pigment in inner ear

Vision and hearing evolved together dating back to the PaxB gene, which is a single gene controlling eye and precursors to hearing (mechanoreceptors) in box jellyfish before independent Pax 2 and Pax 6 genes [40]. There are evolutionary connections between eyes and mechanoreceptors of the inner ear to the extent that during evolution, “sensory cells can shift their sensory modalities” [41].

There is normally melanin pigment in the inner ear [42, 43]. Figure 5A shows band of melanin pigment (P) in a guinea pig cochlea. Figure 5B is a section through a guinea pig cochlea showing melanin pigment (P). Figure 6 displays a microscopic view of area like that in red box in Figure 5B. Red arrows point at capillaries. Melanocytes are adjacent to capillaries in the stria vascularis of inner ear.

Figure 5.

Decalcified guinea pig cochlea (A) and sagittal section (B) through guinea pig cochlea show melanin pigment in stria vascularis. Red boxed area enlarged in Figure 6. From Creel, webvision.med.utah.edu (2014).

Figure 6.

Enlargement of red-boxed area in Figure 5 shows melanin adjacent to capillaries indicated by red arrows. From Creel, webvision.med.utah.edu (2014).

Binaural hearing tells eyes where to look [44, 45]. Spatial vision and auditory localization function in a coordinated manner. From diapsids to mammals interaural sound localization circuits are similarly organized. The auditory map in the brain is like the visual space map [46]. Visual and auditory space interact in the brain. When blind individuals localize auditory echoes, fMRIs reveal more brain activity in visual cortex than auditory cortex [47].

Albino mammals are not hearing impaired. The absence of melanin pigment in the inner ear is associated with susceptibility to noise damage [48, 49, 50]. Also, prolonged sensitivity to noise measured as a longer temporary threshold shift (TTS) following exposure to loud sounds is documented in albinos [51, 52, 53]. In the medial superior olivary nucleus, cell size and dendritic length are decreased in albinos [54]. In albinos component III of auditory brainstem responses is attenuated, which are generated in region of the medial superior olivary nuclei reflecting the reduced neuronal size and dendritic length in albino mammals [54, 55, 56, 57].

The brainstem auditory pathways of albino mammals have anomalies like the visual system. Reduced cell size in brainstem olivary nuclei is associated with reduced binaural cell responses in medial superior olive of albino cats [58] resulting in disruption of sound localization, like finding of reduced binocular cells in visual cortex. Moore & Kowalchuk [59] described reduced ipsilateral projections from the cochlear nuclei in hypopigmented ferrets.

1.3 Creel theory

The Creel theory proposes that the lack of melanin pigment initiates atavistic expression of visual and auditory embryogenesis. Melanin pigment is an environmental cue. Embryonic progression in albino mammals’ visual and auditory systems take a step back initiated by lack of melanin pigment. Abnormalities of chiasmic misrouting in albino mammals is a developmental field defect that is normal in preceding phylogeny [60]. Complete crossing of optic neurons at the chiasm is normal in most vertebrates prior to mammals.

The presence of melanin pigment in the embryonic retina, or possibly genetic coding for melanin pigment, initiates retinal ganglion cell pathway routing. Insufficient coding for retinal pigment launches an earlier, more stable genetic package directing targeting of optic neurons.

Genetic makeup includes preserved earlier evolutionary features. Charles Darwin [61] popularized atavism as the term for reappearance of ancestral characteristics in future generations. Expression of atavistic features, such as complete crossing of optic fibers, is likely due to the flaw in the embryonic environment, in this case, lack of melanin pigment, precipitating formation of an earlier ancestral pathway.

2. Conclusion

Mammals lacking melanin pigment in retina and inner ear have abnormal visual and auditory systems. Mammals preserve the genetic instructions for complete decussation of the retinal ganglion cells at the optic chiasm and presence of melanin pigment adjacent to capillaries in inner ear. Phylogenetically newer genetic directions for formation of a central retinal area, fovea, and vascular sparing of the foveal area are vulnerable. Recent genetic addendums to conserved instructions are at risk if genetic cues, such as sufficient melanin pigmentation, are not present to support variation from ancient instructions. In albino mammals, the genetic instruction for visual pathways defaults to the simpler, more entrenched, platform. The auditory system follows with similar disarray.

Acknowledgments

Supported in part by an Unrestricted Grant from Research to Prevent Blindness, New York, NY, to the Department of Ophthalmology & Visual Sciences, University of Utah.