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(Investigative Ophthalmology and Visual Science. 2000;41:2352-2356.)
© 2000 by The Association for Research in Vision and Ophthalmology, Inc.

Localization of Tubby-like Protein 1 in Developing and Adult Human Retinas

Ann H. Milam1, Anita E. Hendrickson2,3, Ming Xiao2, Julie E. Smith1, Daniel E. Possin3, Sinoj K. John1 and Patsy M. Nishina4

1 From the Scheie Eye Institute, University of Pennsylvania, Philadelphia; the Departments of 2 Biological Structure and 3 Ophthalmology, University of Washington, Seattle; and 4 The Jackson Laboratory, Bar Harbor, Maine.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
PURPOSE. To localize tubby-like protein 1 (TULP1) in developing and adult human retinas.

METHODS. TULP1 was localized by immunofluorescence microscopy in human retinas, aged 8.4 fetal weeks to adult. TULP1-positive cells were identified by double labeling with antibodies specific for cones, rods, and astrocytes.

RESULTS. In adult retinas, anti-TULP1 labels cone and rod inner segments, somata, and synapses; outer segments are TULP1-negative. A few inner nuclear and ganglion cells are weakly TULP1- positive. In fetal retinas, cells at the outer retinal border are TULP1-positive at 8.4 weeks. At 11 weeks, the differentiating central cones are strongly TULP1-reactive and some are positive for blue cone opsin. At 15.4 weeks, all central cones are strongly positive for TULP1 and many are reactive for red/green cone opsin. At 17.4 weeks, central rods are weakly TULP-reactive. In peripheral retina at 15.4 weeks to 1 month after birth, displaced cones in the nerve fiber layer are positive for TULP1, recoverin, and blue cone opsin. Some ganglion cells are weakly reactive for TULP1 at 11 weeks and later, but astrocytes and the optic nerve are TULP1-negative at all ages examined.

CONCLUSIONS. The finding of TULP1 labeling of cones before they are reactive for blue or red/green cone opsin suggests an important role for TULP1 in development. TULP1 expression in both developing and mature cones and rods is consistent with a primary photoreceptor defect in retinitis pigmentosa (RP) caused by TULP1 mutations. Weak TULP1-immunolabeling of some inner retinal neurons in developing and adult retinas suggests that optic disc changes in patients with RP who have TULP1 mutations may be primary as well as secondary to photoreceptor degeneration.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
In tubby mice, also known as retinal degeneration 5 (rd5), a recessive mutation in the tub gene causes progressive retinal and cochlear degeneration and adult-onset obesity with insulin resistance.1 2 The mutation in the tub gene that leads to these phenotypic alterations is a G->T transversion that abolishes a donor splice site, leading to replacement of the carboxyl-terminal 44 amino acids with a 20–amino acid sequence not found in the wild-type protein.3 Tub is a member of a small neuronally expressed gene family that includes human TUB (homologous to mouse tub), tubby-like protein 1 (TULP1), TULP2, and TULP3. The tubby proteins have a highly conserved carboxyl terminal region but divergent amino terminals, and related proteins are found in lower animals and plants. The TUB gene is expressed in multiple human tissues including retina, whereas the TULP1 gene product is found mainly in retina. TULP2 is expressed primarily in testis,4 and TULP3 is found in multiple tissues, including the retina.5 6

Recent evidence suggests that TULP1 is a transcription factor involved in control of downstream genes in retinal photoreceptors.7 Autosomal recessive retinitis pigmentosa (RP) develops in patients homozygous for mutations in the TULP1 gene.8 9 10 11 A recent report of a large family in the Dominican Republic described the phenotype of patients homozygous for a splice site mutation (IVS14 + 1, G->A) in the conserved carboxyl region of TULP1 gene.11 In the first decade of life, the affected persons have nystagmus, absent rod function, and severely impaired cone function throughout the retina. The early vision loss is suggested to result from photoreceptor maldevelopment, dysfunction, or degeneration.11

The Dominican Republic family members with RP also show early optic disc abnormalities suggestive of degenerative changes in the ganglion cells and/or the optic nerve. One study of mouse retina found tub expression restricted to ganglion cells during embryogenesis and mainly in photoreceptors in postnatal and adult animals.12 A more recent study found tub expressed in both ganglion cells and photoreceptors in adult mouse retina.6 The clinical findings, together with the tub expression pattern in retina, raises the question of whether TULP1 is expressed not only in photoreceptors but also in ganglion cells and the optic nerve in developing human retinas.11 Recent studies6 13 demonstrate TULP1-immunolabeling of mouse photoreceptors. However, cones are a minor population in mouse retina, and we wanted to know whether human cones also express this protein. To resolve these questions and provide needed information on the pathophysiology of retinal degeneration caused by TULP1 mutations, we used immunocytochemistry to localize the TULP1 protein in developing and adult human retinas.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Tissue Preparation
Adult human eyes were obtained through the donor programs of the Foundation Fighting Blindness (Hunt Valley, MD) and the University of Washington Lions Eye Bank (Seattle). Fetal human eyes were obtained from the University of Washington Human Embryology Laboratory. The research followed the tenets of the Declaration of Helsinki, and informed consent was obtained from all donors. The research was approved by the institutional human subjects review boards of the University of Washington and the University of Pennsylvania. Eight normal adult retinas were evaluated, all fixed at 6 hours or less after death, along with retinas fixed within 1 hour after death at fetal ages 8.4, 9, 11, 14, 15.4, 17.4, 18, 19, and 21.5 weeks and postnatal ages 3 days and 1 month. The globes were fixed for several weeks to months in 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.3), and stored thereafter in 2% paraformaldehyde in the same buffer.

Immunocytochemistry
Retinal samples were cryosectioned at 12 µm and processed for immunofluorescence according to published techniques.14 The secondary antibodies (goat anti-rabbit or anti-mouse IgG) were labeled with fluorescein isothiocyanate (green), Cy-2 (green), or Cy-3 (red; Jackson ImmunoResearch, West Grove, PA). Nuclei were stained with DAPI (1 µg/ml; Molecular Probes, Eugene, OR). Control sections were treated in the same way with omission of primary antibody.

The anti-TULP1 (TULP1-N) was a rat polyclonal antibody (pAb) against the amino-terminal half of human TULP1,6 used at a dilution of 1:750 to 1:1000. Cell-specific antibodies prepared in rabbits or mice were used for double labeling to analyze the various retinal cell types labeled with anti-TULP1. Rods were identified with anti-rhodopsin, a mouse monoclonal antibody (mAb; 4D2; 1:40; from Robert Molday, University of British Columbia, Vancouver, Canada). Cones were marked with rabbit pAb anti-blue cone opsin (JH455; 1:5000–1:10,000) and anti-red/green cone opsin (JH492; 1:5000–1:10,000; from Jeremy Nathans, Johns Hopkins University, Baltimore, MD). Cones were also labeled with rabbit pAb anti-red/green cone opsin (1:200; from John Saari, University of Washington, Seattle). The rods, cones, and flat midget bipolar cells were identified with rabbit pAb anti-recoverin (1:1000; from Alexander Dizhoor, Wayne State University, Detroit, MI). Astrocytes were labeled with pAb anti-glial fibrillary acidic protein (GFAP; 1:500; Dako, Carpinteria, CA).

Immunolabeled retinal sections were photographed with an epifluorescence microscope (DMR; Leica, Deerfield, IL) using Elite Chrome film (ASA 400; Eastman Kodak, Rochester, NY). Images were digitized with a flatbed scanner (HiRes; Saphir, Heidelberg, Germany) with Elite 5.1 software (LinoColor, Heidelberg, Germany) and imported into a graphics program (Photoshop 5.0; Adobe, San Jose, CA) from which dye-sublimation prints were generated.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Adult Human Retinas
Strong TULP1-immunolabeling was present in rod inner segments, somata, and synapses (Fig. 1A ). TULP1-reactivity was present but somewhat less intense in the cone inner segments, whereas cone somata and synapses were heavily labeled (Fig. 1A) . No TULP1-labeling was found in rod or cone outer segments (Fig. 1A) . Double labeling with anti-TULP1 and anti-recoverin demonstrated absence of TULP1-reactivity in the photoreceptor outer segments but colocalization of both proteins in the cone and rod inner segments, somata, and synapses (Figs. 1B 1C) . A few cells in the inner nuclear and ganglion cell layers were weakly TULP1-positive (Figs. 1A 1D) . Control sections treated with only Cy3-labeled secondary showed autofluorescence of lipofuscin in the retinal pigment epithelium (Fig. 1E) .



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  		Figure 1. Adult human retina, age 56 years. (A) Immunolabeling with anti-TULP1 (red), with DAPI staining (blue) of nuclei. Note labeled photoreceptor (p) inner segments, somata, and synapses and weaker labeling of a few cells in the inner nuclear (n) and ganglion (g) cell layers. (B) Anti-recoverin (green) labeling, with DAPI-stained nuclei. Note intense labeling of photoreceptor outer and inner segments, somata, and synapses and weaker labeling of a few inner nuclear layer cells. (C) Anti-TULP1 (red) and anti-recoverin (green) labeling, with DAPI-stained nuclei. Note outer segment (os) labeling (yellow-green) with anti-recoverin only and colocalization (gold) of TULP1 and recoverin in the photoreceptor (p) inner segments, somata, and synapses. (D) Higher magnification of TULP1-localization. Note TULP1-positive photoreceptor inner segments (i), somata, and synapses, and a few TULP1-positive cells in the inner nuclear layer (n). (E) Control section treated with no primary antibody, with DAPI-stained nuclei. Note intense autofluorescence of the retinal pigment epithelium (r). (F) Section of 11 wk fetal retina labeled with anti-TULP1 with DAPI-stained nuclei. The neuroblast cell nuclei are stained blue with DAPI. Note intense TULP1-labeling of cells (*) lying outermost in the retina. Ganglion cells (g) are also TULP1-positive. Magnification, (A, B, and C) x102; (D, E, and F) x193.

 
Fetal Human Retinas
Because of the steep developmental gradients in early fetal retinas,15 sections were studied that were cut along the horizontal meridian in or near the fovea. All retinal neurons showed a central to peripheral gradient of maturation, and the fetal retinas showed a central to peripheral appearance of TULP1-immunolabeling. At the earliest ages examined, 8.4 and 11 fetal weeks, TULP1-labeling was found in the outermost cells of the central retina lying opposite the retinal pigment epithelium (RPE; Fig. 1F ). The remainder of the neuroblasts, stained intensely blue with DAPI, were weakly TULP1-positive (Fig. 1F) .

By 21.5 weeks, the neuroblast layer in the periphery was much thicker and TULP1-positive throughout (Fig. 2A ). Double labeling with anti-TULP1 and anti-recoverin revealed that the cells reactive for recoverin (presumed photoreceptors) were restricted to the outer half of the neuroblast layer (Fig. 2B) , whereas TULP1-labeling was also found in undifferentiated progenitor cells in the inner neuroblast layer (Fig. 2C) . A thinner layer of cells at the outermost margin of the retina, just opposite the RPE, was intensely reactive for both TULP1 and recoverin (Fig. 2C) .



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  		Figure 2. Fetal human retina, age 21.5 weeks. (A) Section labeled with anti-TULP1, with DAPI-stained nuclei. The neuroblast (n) layer is TULP1-positive, especially the outermost cells (*). (B) Same section as in (A) labeled with anti-recoverin, with DAPI-stained nuclei. Cells in the outer half of the neuroblast layer are recoverin-positive (p, presumed photoreceptors), especially the outermost cells (*). (C) Double exposure of section in (A) and (B) illustrating colocalization (gold) of TULP1 and recoverin in the layer of developing photoreceptors (p), especially the outermost cells (*). (D) TULP1-immunolabeling of differentiating cones (arrow) in peripheral retina. (E) TULP1-labeling of differentiating cones in more central retina, with DAPI-stained nuclei. All differentiating photoreceptors are TULP1-positive, but the cones (arrows) are more intensely labeled than the differentiating rods (r) lying more vitread. Ganglion cells (g) are weakly TULP1-positive, and one cell (arrowhead) in the nerve fiber layer (n) is strongly TULP1-positive. (F) Same section as in (E) labeled with anti-blue cone opsin, with DAPI-stained nuclei. Differentiating cones (arrows) are labeled with both anti-TULP1 (E) and anti-blue cone opsin. Note displaced blue cone opsin–positive cell (arrowhead) in the nerve fiber layer (n). (G) Central retina illustrating layer of columnar photoreceptors (p), all of which are TULP1-positive, particularly the differentiating cones. Note TULP1-positive cell (arrowhead) in the nerve fiber layer (n). (H) Section labeled with anti-TULP1, with DAPI-stained nuclei. Note TULP1-positive cells (arrowheads) in the nerve fiber layer (n). (I) Same section as in (H) labeled with anti-recoverin, with DAPI-stained nuclei. Note colocalization of recoverin and TULP1 in the same cells (arrowheads) in the nerve fiber layer (n). Magnification, (A, B, C, E, F, G, I) x193; (D) x290; (H) x193.

 
In the retina at fetal week 17.4 and later, there was a prominent layer of differentiating photoreceptors in both central and peripheral retina, all of which were reactive for both TULP1 (Figs. 2D 2E 2F 2G) and recoverin. Among these cells, some had large, prominent cell bodies that protruded into the subretinal space (Figs. 2D 2E) and a basal process typical of immature cones.16 These differentiating cones were intensely positive for TULP1, and at 11 weeks and later, some were reactive for blue cone opsin (Fig. 2F) . The first cones labeled with anti-red/green cone opsin were found at age 15.4 weeks, and they were also strongly positive for TULP1 (not shown). By 17.4 weeks, all cones in the centralmost retina were intensely TULP1-positive (Fig. 2G) . At this time, the differentiating rods around the developing fovea formed a layer vitread to the differentiating cones, but these early rods were only weakly reactive for TULP1 (Fig. 2E) .

A second group of TULP1-positive cells was found in the developing retinas at fetal age 15.4 weeks to 1 month after birth. These cells lay in the nerve fiber and ganglion cell layers and were often found in small groups, particularly in the peripheral retina (Figs. 2E 2G 2H) . These cells were larger than the neighboring ganglion cells and were round or oval with numerous fine processes. The location and morphology of these cells suggested initially that they were astrocytes, and double labeling was therefore performed with anti-TULP1 and anti-GFAP. Although numerous stellate astrocytes were labeled with anti-GFAP, the TULP1-reactive cells in the innermost retina were GFAP-negative. The multipolar TULP1-reactive cells were labeled with anti-recoverin (Fig. 2I) , and some were reactive with anti-blue cone opsin (Fig. 2F) , but not with anti-red/green cone opsin or anti-rhodopsin. Similar recoverin-positive multipolar cells have been described in the ganglion cell and nerve fiber layers of fetal human retinas,17 although cone-specific markers were not used in that study.

Because of the optic disc abnormalities observed in young human RP patients with TULP1 mutations, it was anticipated that ganglion cells and the optic nerve head might show immunolabeling with anti-TULP1. Scattered cells in the ganglion cell layer were weakly TULP1-positive from 11 weeks onward (Figs. 1F 2E 2G) ; however, they were always less intensely labeled than the differentiating photoreceptors in the same area. In adult retinas, a few ganglion cells and inner nuclear layer cells were also weakly TULP1-positive (Figs. 1A 1D) . The optic nerve head and astrocytes, evaluated with anti-GFAP, were consistently negative for TULP1 (not shown).

Postnatal Human Retinas
The pattern of TULP1-labeling in the newborn (3 day and 1 month) retinas was essentially the same as in the adult. Strong TULP1-reactivity was found in the cone and rod inner segments, somata, and synapses, and a few inner nuclear layer and ganglion cells were weakly labeled. In the periphery, TULP1- and recoverin-positive cells were present in the nerve fiber layer, and a few of these were reactive for blue cone opsin. The optic nerve head and astrocytes were TULP1-negative.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present study documents the localization of TULP1 in developing and adult human retinas. The finding of very early expression of TULP1 by retinal neuroblasts at 8.4 fetal weeks (the earliest age examined) suggests a fundamental role for TULP1 in retinal differentiation. Further, the observation that all retinal neuroblasts were TULP1-positive indicates that this protein may be involved in development of both photoreceptors and inner retinal neurons. TULP1-labeling was strongest in developing cones, including displaced blue cones in the nerve fiber layer, whereas in adult retinas the labeling was somewhat less intense in cones than in rods. The significance of these cone/rod differences is unknown but suggests that both populations of photoreceptors are probably affected early in development of the retina in RP patients with mutations in the TULP1 gene. In agreement, recent studies of patients homozygous for a TULP1 mutation11 and TULP1-/- mice13 have documented early degenerative changes in the cones as well as the rods.

Many genes associated with human RP are expressed solely in photoreceptors, the cells that usually undergo primary degeneration.18 Older patients with RP often show optic disc changes consistent with secondary degeneration of ganglion cells and their axons.19 Sahly et al.12 found tub expression in ganglion cells during mouse retinal embryogenesis but mainly in photoreceptors in postnatal and adult mice. The observation that the Dominican Republic patients with RP who are homozygous for a splice-site mutation in the TULP1 gene can show optic disc degeneration in the first decade of life raised the question of whether TULP1 is expressed in inner retinal neurons as well as photoreceptors during development.11 Findings from the present immunolabeling study favor this supposition, because TULP1-labeling was detected in differentiating ganglion cells early in retinal development and in a few of these cells in adult retinas.

The absence of TULP1-labeling in cone and rod outer segments found here in human retinas and also in wild-type mouse retinas6 13 suggests that this protein does not play a role in phototransduction. It is critical to identify the genes regulated by TULP1 as a possible transcription factor7 to understand the degenerative changes in photoreceptors and inner retinal neurons in RP caused by mutations in the TULP1 gene.


   Acknowledgements
 
The authors thank the scientists listed in the Methods section for providing antibodies, and Andra Erickson for help with the sectioning.


   Footnotes
 
Supported by the Foundation Fighting Blindness, Hunt Valley, Maryland (AHM and PMN); the Paul and Evanina Bell Mackall Foundation Trust, New York, New York (AHM); National Institutes of Health Grants EY04536 and EY01730 (AEH); the Kayser Award (AEH); and AXYS Pharmaceuticals (PMN).

Submitted for publication November 19, 1999; revised January 6, 2000, and February 7, 2000; accepted February 15, 2000.

Commercial relationships policy: N.

Corresponding author: Ann H. Milam, Scheie Eye Institute, 51 North 39th Street, Philadelphia, PA 19104. annmilam{at}mail.med.upenn.edu


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Heckenlively, J, Chang, B, Erway, L, et al (1995) Mouse model for Usher syndrome: linkage mapping suggests homology to Usher type I reported at human chromosome 11p15 Proc Nat Acad Sci USA 92,11100-11104[Abstract/Free Full Text]
  2. Ohlemiller, K, Hughes, R, Lett, J, et al (1997) Progression of cochlear and retinal degeneration in the tubby (rd5) mouse Audiol Neurootol 2,175-185[Medline][Order article via Infotrieve]
  3. Noben–Trauth, K, Naggert, J, North, M, Nishina, P. (1996) A candidate gene for the mouse mutation tubby Nature 380,534-538[Medline][Order article via Infotrieve]
  4. North, M, Naggert, J, Yan, Y, et al (1997) Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases Proc Nat Acad Sci USA 94,3128-3133[Abstract/Free Full Text]
  5. Nishina, P, North, M, Ikeda, A, et al (1998) Molecular characterization of a novel tubby gene family member, TULP3, in mouse and humans Genomics 54,215-220[Medline][Order article via Infotrieve]
  6. Ikeda, S, He, W, Ikeda, A, et al (1999) Cell-specific expression of tubby gene family members (tub, TULP1, 2, and 3) in the retina Invest Ophthalmol Vis Sci 40,2706-2712[Abstract/Free Full Text]
  7. Boggon, TJ, Shan, W-S, Santagata, S, et al (1999) Implication of tubby proteins as transcription factors by structure-based functional analysis Science 286,2119-2125[Abstract/Free Full Text]
  8. Banerjee, P, Kleyn, P, Knowles, J, et al (1998) TULP1 mutation in two extended Dominican kindreds with autosomal recessive retinitis pigmentosa Nat Genet 18,177-179[Medline][Order article via Infotrieve]
  9. Gu, S, Lennon, A, Li, Y, et al (1998) Tubby-like protein-1 mutations in autosomal recessive retinitis pigmentosa Lancet 35,1103-1104
  10. Hagstrom, S, North, M, Nishina, P, et al (1998) Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa Nature 18,174-176
  11. Lewis, C, Batlle, I, Batlle, K, et al (1999) Tubby-like protein 1 homozygous splice-site mutation causes early-onset severe retinal degeneration Invest Ophthalmol Vis Sci 40,2106-2114[Abstract/Free Full Text]
  12. Sahly, I, Gogat, K, Kobetz, A, et al (1998) Prominent neuronal-specific tub gene expression in cellular targets of tubby mice mutation Hum Mol Genet 7,1437-1447[Abstract/Free Full Text]
  13. Hagstrom, SA, Duyao, M, North, MA, Li, T. (1999) Retinal degeneration in tulp1-/- mice: vesicular accumulation in the interphotoreceptor matrix Invest Ophthalmol Vis Sci 40,2795-2802[Abstract/Free Full Text]
  14. Li, Z-Y, Kljavin, IJ, Milam, AH (1995) Rod photoreceptor neurite sprouting in retinitis pigmentosa J Neurosci 15,5429-5438[Abstract]
  15. Hendrickson, A. (1992) A morphological comparison of foveal development in man and monkey Eye 6,136-144
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  17. Yan, X, Wiechmann, A. (1997) Early expression of recoverin in a unique population of neurons in the human retina Anat Embryol 195,51-63[Medline][Order article via Infotrieve]
  18. Milam, AH, Li, Z-Y, Fariss, RN (1998) Histopathology of the human retina in retinitis pigmentosa Prog Retinal Eye Res 17,175-205[Medline][Order article via Infotrieve]
  19. Stone, JL, Barlow, WE, Humayun, MS, et al (1992) Morphometric analysis of macular photoreceptors and ganglion cells in retinas with retinitis pigmentosa Arch Ophthalmol 110,1634-1639[Abstract/Free Full Text]



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