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2010 Focus on Fellows Abstracts


A Mutation in ZNF513, a Putative Regulator of Photoreceptor Development, Causes Autosomal-Recessive Retinitis Pigmentosa

Lin Li1,4, Naoki Nakaya2, Venkata R.M. Chavali5, Zhiwei Ma1, Xiaodong Jiao1, Paul A. Sieving3, Sheikh Riazuddin6,7, Stanislav I. Tomarev2, Radha Ayyagari5, S. Amer Riazuddin6,8, J. Fielding Hejtmancik1

1Ophthalmic Molecular Genetics Section, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health; 2Section of Molecular Mechanisms of Glaucoma, Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health; 3National Eye Institute, NIH; 4State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, China; 5Department of Ophthalmology, University of California San Diego, Jacobs Retina Center; 6National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan; 7Allama Iqbal Medical College, Lahore, Pakistan; 8The Wilmer Eye Institute, Johns Hopkins University School of Medicine

Retinitis pigmentosa (RP) is a phenotypically and genetically heterogeneous group of inherited retinal degenerations characterized clinically by night blindness, progressive constriction of the visual fields, and loss of vision, and pathologically by progressive loss of rod and then cone photoreceptors. Autosomal-recessive RP (arRP) in a consanguineous Pakistani family previously linked to chromosome 2p22.3-p24.1 is shown to result from a homozygous missense mutation (c.1015T>C [p.C339R]) in ZNF513, encoding a presumptive transcription factor. znf513 is expressed in the retina, especially in the outer nuclear layer, inner nuclear layer, and photoreceptors.

Knockdown of znf513 in zebrafish reduces eye size, retinal thickness, and expression of rod and cone opsins and causes specific loss of photoreceptors. These effects are rescued by coinjection with wild-type (WT) but not p.C339R-znf513 mRNA. Both normal and p.C339R mutant ZNF513 proteins expressed in COS-7 cells localize to the nucleus.

ChIP analysis shows wild type and mutant Znf513 bind to the Crx promoter, while wt but not mutant ZNF513 interacts with Pax6, Sp4, Arr3, Irbp, and photoreceptor opsin promoters directly, These results suggest that the ZNF513 p.C339R mutation is responsible for RP in this family and that ZNF513 plays a key role in the regulation of photoreceptor-specific genes in retinal development and photoreceptor maintenance.

REEP6 Plays a Role in Neuronal Architecture and Photoreceptor Development

Shobi Veleri1, Trevor J. Foskett1, Edwin Oh3, Brian Lee1, Jacob Nellissery1, Milton A. English1, Raman Sood2, Paul Liu2, Anand Swaroop1,3

1Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health; 2National Human Genome Research Institute, National Institutes of Health; 3Department of Ophthalmology and Visual Sciences, University of Michigan

The transcription factor Neural Retina Leucine zipper (NRL) plays a pivotal role in the rod photoreceptor development and homeostasis. Reep6 is among the genes that are prominently down regulated in the absence of NRL, indicating its role in rod photoreceptors. In olfactory neurons, Sato et al. (2004) suggested that REEP family of proteins might be involved in trafficking of vesicles carrying GPCRs to the plasma membrane. Therefore, we hypothesized that Reep6 has a similar function in rhodopsin transport during replacement of rod outer segments.

Histological examination using Reep6-specific antibody demonstrated its expression in the rods and in cortical and hippocampal neurons. Sub-cellular localization using a fluorescently tagged Reep6 showed that the protein is a resident of endoplasmic reticulum (ER). To elucidate the molecular function of Reep6, we performed shRNA knockdown (KD) in the hippocampal neurons. Our data show that KD of Reep6 led to increased dendritic branching and neurite outgrowth, whereas its over-expression resulted in neurite retraction. We then conducted KD experiments in zebrafish using anti-sense morpholinos. These experiments showed that Reep6 KD altered lamination of the retina. We are now generating a Reep6-KO mouse. Our data indicate that Reep6 plays a role in neuronal architecture maintenance and photoreceptor development.

Structural & Functional Changes in the Hibernating Ground Squirrel Photoreceptor Ribbon Synapse

Jodie Pope1, Shan Chen1, Cole Graydon2, Fengyu Qiao1, Bechara Kachar2, Wei Li1

1Unit on Retinal Neurophysiology, National Eye Institute, NIH; 2 Laboratory of Cell Structure and Dynamics, National Institute of Deafness and Communication Disorders, National Institutes of Health

The synaptic ribbon is a key synaptic structure for many sensory neurons1. In the hibernating ground squirrel retina, photoreceptor synaptic ribbons undergo dramatic morphological changes that are quickly restored upon waking2. In each cone terminal, a large amount of ribbon proteins disengage from the active zone and aggregate into a sphere that resides several microns above the base of the photoreceptor terminal. It is of much interest to determine the necessity/mechanism(s) behind such dramatic structural changes. Direct whole-cell voltage-clamp recordings from off center bipolar cells in control and hibernating ground squirrel retina show a significant reduction in the frequency of miniature excitatory postsynaptic currents (mEPSCs) yet no change in the amplitude or kinetics, indicative of a decrease in presynaptic neurotransmitter release. We set out to examine whether the decreased frequency of mEPSCs is due to the change of the presynaptic spontaneous release probability or the change of releasable vesicle pool size. Since intracellular [Ca2+] ([Ca2+]i) effects the presynaptic spontaneous release probability, we investigated changes in resting intracellular [Ca2+] ([Ca2+]0) and [Ca2+]i handling in hibernating photoreceptors. Live Ca2+ imaging shows during hibernation [Ca2+]0 is significantly higher. Meanwhile, Ca2+ extrusion by plasma membrane Ca2+ ATPase (PMCA) is significantly reduced and mitochondria Ca2+ sequestration is decreased in cone photoreceptor terminals. This data indicates that [Ca2+]0 is possibly higher during hibernation due to the decreased ability of the photoreceptor to extrude and sequester [Ca2+]i via energy-dependent processes. We then estimated the change of the readily-releasable vesicle pool size in hibernating tissues. We found that the readily releasable pool (RRP) of vesicles at the cone ribbon synapse is significantly reduced during hibernation. Electron microscopy further illustrates the reduction in ribbon size and hence RRP size in the hibernating retina. We thus hypothesize that the observed structural changes in the synaptic ribbon during hibernation is a mechanism for maintaining low neurotransmitter release in the presence of high [Ca2+]0. Such adaptive synaptic plasticity may be a strategy to alleviate the unnecessary energy burden of high frequency spontaneous vesicle release at the photoreceptor terminals during hibernation.

A Simple Lipid Compound LC01 Suppresses 7-Ketocholesterol Induced Inflammatory Responses and Cytotoxicity in ARPE19 cells

Jiahn-Dar Huang, Jung Wha Lee, Ignacio M. Larrayoz, Ignacio R. Rodriguez

Mechanisms of Retinal Diseases Section, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health

7-ketocholesterol (7KCh) is an oxysterol known to be involved in the formation of atherosclerotic plaques. In vitro studies have shown that 7KCh induces cytotoxicity and inflammatory responses in various cell types. Previously, we have found that 7KCh is present in the retina associated with oxidized lipoprotein deposits in Bruch’s membrane and choroid. This lipoprotein accumulation has been shown to increase as a consequence of aging. 7KCh is a potent inducer of VEGF and may play an important role in the development of “wet” age-related macular degeneration (AMD), which is characterized by choroidal neovascularization. In the current study, we present a simple lipid compound (LC01) that attenuates 7KCh-mediated cytotoxicity better than other similarly structured controls (SSCs). LC01 suppresses the induction and activation of NF-?B caused by 7KCh treatment. Subsequently, LC01 significantly suppresses the 7KCh-mediated induction of IL-6, IL-8, TNF-a, and VEGF but not IL-1ß. By contrast, the SSCs did not show these anti-inflammatory effects. In a previous study, our group demonstrated that 7KCh induces inflammatory responses by activating three NF-?B related pathways: ERK, p38 MAPK, and Akt-PKC?- NF-?B. However, LC01 does not seem to inhibit the 7KCh-mediated inflammation and cytotoxicity via these pathways since both LC01 and SSCs showed similar effects on the phosphorylation of these kinases. In summary, although the pharmacological mechanisms remain to be determined, LC01 shows high potential as an anti-inflammatory agent and as a target for future drug development to treat “wet” AMD and atherosclerosis.

Mapping Visual Activity in Frontal Cortex

Wilsaan M Joiner, James Cavanaugh, and Robert H Wurtz

Visuomotor Integration Section, Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health

The presence of a suppressive surround has been demonstrated in numerous cortical and subcortical visual and visuomotor areas. Here we studied the suppressive surround in monkey frontal cortex (Frontal Eye Field, FEF). After determining the location and extent of the neuron's excitatory receptive field (RF), we activated the suppressive surround by expanding a spot of light beyond the excitatory region of the RF. Responses to larger stimuli reduced visual responses, reflecting the interaction between excitatory and suppressive components of the RF. We fit diameter-tuning curves with a Difference of Gaussians and estimated the diameter of the excitatory and suppressive components (the peak and asymptote of the fit curve respectively). The mean diameter of the excitatory center and suppressive surround increased with eccentricity. The diameter of the suppressive component was between 2.5 to 11 times larger than the excitatory component and the surround suppressed visual responses by an average of 69%. We also examined whether the excitatory and suppressive components of the RF were regulated independently by differential stimulation of the surround while stimulating the central excitatory component. We compared the surround's effect on the center by expanding surround stimulation out from the center (an expanding spot) and by increasing surround stimulation in from the RF periphery (an inward constricting annulus). We found that neuronal responses were dependent on the configuration of the visual stimulus: stimulating an area of visual space close to the excitatory component could increase or decrease the visual response of the neuron dependent upon what other areas of the surround were simultaneously stimulated. This suggests that the effect of visual stimuli in FEF depends on the balance between the activity of the excitatory and inhibitory RF components.

Changes in Retinal Sensitivity in Geographic Atrophy Progression as Measured by Microperimetry

Annal .D. Meleth1, Pradeep Mettu1, Frederick L. Ferris, III1, Emily Y. Chew1, Wai T. Wong2

1Division of Epidemiology and Clinical Applications and 2Unit on Neuronal-Glial Interactions in Retinal Disease, National Eye Institute, National Institutes of Health

Geographic atrophy (GA) represents the advanced atrophic form of age-related macular degeneration. As there is currently no effective treatment for GA to either prevent its onset or progression, clinical trials employing useful and relevant outcome measures in the discovery of a treatment are of important public health significance. We measured retinal sensitivity using the Nidek Microperimetry device over time in the context of the OTHERA trial for anti-oxidant eye drops for GA. Retinal sensitivity in the macular area was evaluated by microperimetry in 10 patients with bilateral GA, with adequate data obtained in 9/10 patients (n = 18 eyes). Microperimetric assessments were performed every 6 months over 24 months. Microperimetric parameters analyzed included the number of scotomatous points, mean retinal sensitivity of responding points in both peri- and extra-lesional areas, and fixation stability. A mixed model was used to analyze the change in these parameters over time. We found statistically significant changes in retinal sensitivity were detected over the 2-year period of GA progression. The mean number of scotomatous points increased by 4.3 points per year (p=0.0004). Mean retinal sensitivity of all points, all responding points and perilesional points, all decreased significantly (p<0.0001). Mean sensitivity of responding points decreased at a rate of 1.1 dB/year. The quality of fixation within the 2º and 4º circle also declined significantly over time (p<0.002). The rate of increase of scotomatous points was also correlated with the rate of increase of GA area as measured from fundus autofluorescence images (p=0.01). The natural history of GA progression over time is evident in progressive changes in retinal sensitivity as measured by microperimetry. Microperimetry may be a useful adjunctive assessment modality in following visual function of patients with GA and may contribute outcome measures for interventional studies.

Innate Production of Regulatory Cytokines Contributes to the Outcome of Experimental Autoimmune Uveitis (EAU)

Anna M Hansen1, Aleksandra Rachitskya1, Reiko Horai1, Katrin D. Mayer-Barber2, Rafael Villasmil1, Phyllis Silver1 and Rachel R Caspi1

1Laboratory of Immunology, National Eye Institute and 2Laboratory of Parasitic Diseases, National Institute of Allergies and Infectious Diseases, National Institutes of Health

The innate immune response is characterized by low antigen specificity and the rapid production of large amounts of inflammatory cytokines, and is primarily thought of as a “first line of defense” against infection. However, the cytokine milieu it generates also plays an important role in the differentiation and function of antigen-specific T cells as they are activated. We found that induction of innate IFN-? early in the immune response protects from development of EAU by inhibiting adaptive IFN-? and IL-17 responses. Interestingly, innate production of IFN-? and IL-17 by mouse strains differing in susceptibility to EAU appear to be inversely correlated, with the most resistant strain (Balb/c) skewed to high IFN? production and the most susceptible strain (B10RIII) skewed to IL-17.

In experiments designed to dissect the cellular origin and regulation of innate IL-17, we observed that invariant NKT cells rapidly produced IL-17 in the presence of IL-23 in a STAT-3 dependent fashion, but unlike in the adaptive Th17 response, IL-6 signaling was not required. IL-6/IL-21R-/- (DKO) mice were used to determine whether IL-21 was compensating for IL-6 (as reported for adaptive IL-17) and while these mice failed to develop adaptive Th17 responses and EAU, their innate IL-17 production was undiminished. Unexpectedly, a non-NKT IL-17 producing population of T cells with a memory phenotype was present not only in WT mice, but also in DKO mice that completely lack an adaptive IL-17 response. These innate IL-17 producers appear to be a new, previously unrecognized T cell subset that does not express CD4, CD8 or the NK markers DX5 or NK1.1, and does not bind aGalCer-CD1d tetramers. These cells are poor producers of IFN-? and account for virtually all IL-17 production within the memory T cell compartment of naïve mice. Their ability to proliferate rapidly and tremendous potential for IL-17 production suggest they may be relevant to the development of IL-17-related pathologies such as EAU.

Subconjunctival Sirolimus for the Treatment of Active Anterior Uveitis

Theresa Larson1, Annal Meleth2, Wendy M. Smith1, Dominic Obiyor3, Robert B. Nussenblatt1, H. Nida Sen1

1Clinical Immunology Section, Laboratory of Immunology, 2Division of Epidemiology and Clinical Applications, and 3Office of the Clinical Director, National Eye Institute, National Institutes of Health

Purpose: To evaluate the safety and possible efficacy of subconjunctival sirolimus injection for the treatment of active recalcitrant anterior uveitis

Methods: This prospective, unmasked, open-label pilot trial included five patients with active anterior uveitis despite treatment with topical steroids and/or systemic immunosuppressives. Study drug was administered as one-time subconjunctival injection of 30µL (1,320µg) sirolimus at baseline visit. Study visits were performed at baseline, 2 weeks, 4 weeks, and monthly thereafter until 4 months and included a complete ophthalmic exam at each visit, physical exam, and ancillary ophthalmic testing at some visits. Primary outcome measure was a 2-step reduction in the anterior chamber inflammation within 4 weeks of injection of the study drug.

Results: Five patients with active anterior uveitis have been enrolled in this pilot clinical trial between 2009 and 2010. There were 3 female and 2 males, 4 were idiopathic anterior uveitis, and one was psoriatic arthritis associated. Three of the five patients met the primary outcome criteria by showing at least 2-step decrease in inflammation within 4 weeks, 2 patients showed 1 step decrease in inflammation within the same time frame. No recurrence was encountered during a 4-month follow-up. There were no serious adverse events.

Conclusions: Subconjunctival sirolimus injection appears to help reduce active inflammation in patients with active recalcitrant anterior uveitis. It can be particularly useful in patients with contraindication to local steroid injections.

Visual Striatum and Object-based Saccadic Behavior

Shinya Yamamoto, Masaharu Yasuda, Ilya E. Monosov, Okihide Hikosaka

Neuronal Networks Section, Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health

We understand the world by seeing our surroundings. To do so, we incessantly make saccadic eye movements (saccades) to various objects, especially to ‘important’ objects. Although basic neuronal circuits for initiating saccades are well understood, it is unclear which brain area evaluates individual objects and uses the information to induce saccades. To do so requires: 1) encoding of both "what" and "where" information about objects, and 2) adaptability based on past experience. A first candidate is the posterior part of the striatum (PS; caudate tail and the posterior putamen), as it has been anatomically shown to 1) receive inputs from visual cortical areas (temporal and parietal cortex), 2) send outputs to motor executive structures, and 3) receive dopaminergic inputs. To test this hypothesis, we recorded electrical signals from single PS neurons while monkeys were performing an object-directed saccade task. We created many visual objects using fractal geometry. On each trial, one of the fractal pictures was presented at one of 5 positions (right, left, up, down, and center). Monkeys made a saccade to the fractal picture to obtain a fixed amount of liquid reward. Many PS neurons responded to the fractal pictures, and did so in position-selective and object-selective manners (e.g., only downward position and only 2 of 8 objects). To test adaptability of PS neurons, we trained monkeys using the object-directed saccade task, but half of the fractal pictures were followed by reward and the other half were followed by no reward. After several days of training, the visual responses of PS neurons to the rewarded fractals became stronger than those to the non-rewarded fractals. These data suggest that PS plays an important role in the adaptable object-based saccadic behavior, which is modulated by past experience of rewards.

Fat1 Protocadherins are Critical in Optic Fissure Closure

Sanita Bharti1, Kapil Bharti3, Felix Onojafe1, Jacob D. Brown1, Chi Chao Chan2 and Brian P. Brooks1

1 Pediatric, Developmental and Genetic Ophthalmology Section, Ophthalmic Genetics and Visual function Branch, and 2Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health; 3National Institute of Neurological Disorders and Stroke, National Institutes of Health

This study investigates the role of Fat protocadherins in ocular development. Previous work done in this lab suggested that Fat protocadherins were dynamically regulated at the closing edges of the optic fissure—a process that, when faulty, results in a potentially blinding congenital ocular malformation, uveal coloboma. Two members of the Fat protocadherin family, namely Fat1 and Fat4 have previously been shown to affect cell migration and tissue organization in the planar cell polarity (PCP) pathway, respectively. Both Fat1 and Fat4 are dynamically expressed in the optic cup and lens of the developing mouse eye at and around the time of optic fissure closure. An in-depth analysis of the ocular phenotype of Fat1 and Fat4 knockout mice revealed that, while the Fat4 knockout mice do not exhibit a robust ocular phenotype, 80-90% of Fat1-/- E14.5 mouse embryos had bilateral uveal coloboma. Preliminary histopathology from these embryos suggests abnormal tissue organization and cell architecture. However, very early eye development and patterning does not appear to be grossly affected, since early markers such as Mitf, Pax2, Pax6 and Chx10 seem to be unaffected in knockout embryos. These initial observations are leading us to further explore the role of cell migration, proliferation, and tissue organization in optic fissure closure.

Interaction of Complement Factor H and EFEMP1/Fibulin3 in Age-related Macular Degeneration

Sanghamitra Mishra1, Keith Wyatt1, Jen-Yue Tsai2, Robert N. Fariss2, Steven Bernstein3, and Graeme Wistow1

1Section on Molecular Structure and Functional Genomics and 2Biological Imaging Core, National Eye Institute, National Institutes of Health; 3Departments of Ophthalmology and Neurobiology & Genetics, University of Maryland School of Medicine

A common sequence variant (Y402H) in the seventh domain of complement factor H (CFH) is associated with increased risk for age-related macular degeneration (AMD), a major cause of blindness in aging populations. Yeast 2-hybrid (Y2H) screening of aged human retinal pigment epithelium (RPE)/choroid showed that CFH domain 7 binds the C-terminal region of EFEMP1/Fibulin 3 (Fib3), with the H variant showing higher affinity. Binding of recombinant constructs for CFH domains 6-8 and the C-terminal region of Fib3 was examined by ELISA and again the disease risk associated H variant of CFH showed higher binding affinity. Native CFH and Fib3 interact and co-immunoprecipitate from solution. Fib3 is mutated in Malattia leventinese/Doyne honeycomb retinal dystrophy, an AMD-like inherited macular degeneration, and is also expressed abnormally in macular RPE in AMD. Fib3 is also induced in ARPE-19 cells by serum-starvation. Immunofluorescence labeling of human AMD donor eye revealed colocalization of CFH and Fib3 in ‘soft’ drusen (deposits basal to the RPE that are associated with development of AMD) but not in the more common ‘hard’ drusen or in normal retina. Direct interaction between Fib3 and CFH at the RPE/choroid interface may be a key step in formation of soft drusen and the cascade of events, including local dysregulation of complement, which leads to vision loss in AMD. This interaction connects systemic and tissue-specific features of AMD risk and provides a new target for therapeutic intervention.

Regulation of the Major Photoreceptor Transcription Factor NRL during Retinal Development

Marie-Audrey Kautzmann, Douglas. S. Kim, Jerome Roger, Hong Hao, Anand Swaroop

Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health

Purpose: NRL is a bZIP transcription factor that controls rod versus cone cell fate decision during retinal development. NRL is essential and sufficient for rod differentiation and homeostasis. Photoreceptor-specific expression of NRL provides an excellent model to delineate genetic regulatory networks during development. This study aims at understanding how expression of the mouse Nrl gene is regulated during retinal development.

Methods: Putative mouse Nrl promoter/enhancer sequences were identified by in silico analysis of inter-species conservation of genomic sequences upstream of the Nrl transcription start site (TSS). The relevant genomic region was cloned in the pEGFP-N1 vector. The plasmid constructs were electroporated in newborn CD1 mouse retina, and GFP reporter gene expression was assessed at P14. In silico analysis also identified transcription factor binding sites in conserved Nrl promoter regions. The binding of candidate transcription factors is being assessed by EMSA using nuclear extracts from P0-2 and adult mouse retina. Promoter sequences are being investigated by luciferase reporter assays in vitro.

Results: Except for the 0.4 kb construct, the three larger constructs faithfully produced GFP expression specifically in the rods. In silico study revealed binding sequences for bHLH proteins and several transcription factors that might play a role in photoreceptor development. Identity of specific cis-regulatory elements and DNA binding proteins is being evaluated by EMSA and luciferase assays.

Conclusions: Our data show that the regulatory sequences necessary for the rod photoreceptor specific expression of Nrl are located between 0.4 kb and 2.8 kb of upstream region. Identification of specific Nrl regulators will lead to better understanding of regulatory networks that dictate the genesis of photoreceptors from multipotent retinal progenitors.

Multiple Roles of Glaucoma-associated Myocilin Protein

Heung-Sun Kwon, Thomas V. Johnson, Stanislav I. Tomarev

Molecular Mechanisms of Glaucoma Section, Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health

Glaucoma, a group of chronic optic neuropathies characterized by the death of retinal ganglion cells, degeneration of the optic nerve, and progressive visual field loss, is a leading cause of irreversible blindness in the world. It is now well established that mutations in the MYOCILIN gene may lead to glaucoma; indeed, they account for more than 10% of juvenile open-angle glaucoma cases and in 3-4% of patients with adult onset primary open-angle glaucoma. However, the functions of wild-type myocilin are still unclear. The current study was conducted to investigate ocular and non-ocular functions of myocilin.

We demonstrated that myocilin, similar to Wnt proteins, interacts with the cysteine-rich domains of several frizzled receptors, with secreted frizzled-related proteins, and with Wnt inhibitory factor WIF-1. These interactions involving myocilin appear to modify the organization of actin cytoskeleton, stimulate the formation of stress fibers and cell migration, and could play a key role in the contractility of the trabecular meshwork for intraocular pressure regulation. We suggest that myocilin may serve as a modulator of Wnt signaling.

In addition, we showed that sciatic nerve is one of the non-ocular sites of myocilin expression. Myocilin is expressed by myelinating Schwann cells and accumulates at the nodes of Ranvier where it interacts with several protein components of the nodes including gliomedin and neurofascin. Addition of myocilin to cultures of dorsal root ganglion neurons stimulated clustering of nodal components including neurofascin and ankyrin G. The formation of nodal clusters is less efficient in myocilin knockout mice. We speculate that myocilin may participate in the regulation of saltatory conduction in the peripheral nervous system.

We concluded that myocilin has multiple ocular and non-ocular functions and that the MYOCILIN gene represents an example of gene sharing.

Department of Health and Human Services NIH, the National Institutes of Health