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(Investigative Ophthalmology and Visual Science. 2001;42:2125-2129.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

Expression of the Insulin Receptor in the Retina of the Goldfish

Peter F. Hitchcock1, Deborah C. Otteson2 and Paul F. Cirenza1

1 From the Departments of Ophthalmology and Visual Sciences and Cell and Developmental Biology, The University of Michigan, Ann Arbor, Michigan; and 2 Wilmer Eye Institute, Baltimore, Maryland.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. Insulin is a peptide growth factor that is active in most tissues, both during development and in adulthood. The action of insulin is through its specific membrane receptor. Previously retinal progenitors in the adult goldfish were shown to proliferate vigorously when exposed to insulin in vitro.1 The present study was undertaken to clone and characterize partial cDNAs that encode the goldfish’s insulin receptor (IR) and to establish the cellular pattern of expression of this gene in the retina.

METHODS. Standard methods were used for RNA isolation, reverse transcription–polymerase chain reaction, Northern blot analysis, and in situ hybridization.

RESULTS. Multiple clones were isolated that, based on sequence analysis, segregated into two groups, presumed to represent two genes that encode the IR. These clones were designated goldfish IR-1 (gfIR-1) and goldfish IR-2 (gfIR-2). Northern blot analysis showed that both genes are expressed in multiple tissues, including the retina. Both gfIR-1 and -2 give rise to a single, major transcript, but the sizes of the two transcripts are different. In situ hybridizations using digoxygenin-labeled riboprobes showed that gfIR-1 and -2 are expressed by all differentiated retinal neurons as well as neuronal progenitors in the circumferential germinal zone.

CONCLUSIONS. These data demonstrate that the IR is expressed in the retina of the goldfish, and, on the basis of the cellular pattern of expression, suggest that insulin may act both to regulate neurogenesis and influence the function of differentiated neurons. The cellular coexpression of the receptors for both insulin-like growth factor (IGF) 1 and insulin suggests that neurons and/or neuronal progenitors in the retina of the goldfish may contain hybrid IGF-1/insulin receptors.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The retina of teleost fish is a popular model for studying the development, plasticity, and regeneration of the central nervous system. The retina of the goldfish grows continually by both a balloon-like expansion2 and the addition of new neurons.3 4 5 New neurons, with the exception of rod photoreceptors, are generated from an annulus of retinal progenitors, known as the circumferential germinal zone (CGZ), that resides at the junction of the retina and iris. Rod photoreceptors are produced interstitially and once born are insinuated into the existing array of photoreceptors.6 In addition to this persistent, growth-associated neurogenesis, the retina will regenerate if injured.7

In an attempt to identify molecules that regulate growth-related and injury-induced neurogenesis in fish, Boucher and Hitchcock1 tested numerous peptide growth factors and found that those structurally related to insulin (insulin, insulin-like growth factor [IGF] 1and IGF-2) are potent mitogens of retinal progenitors within the CGZ. The proliferative response to these peptides was robust and dose dependent. The study described here was undertaken confirm that the mitogenic activity of insulin1 is via the insulin receptor (IR). To this end, partial cDNAs encoding the IR in the goldfish were cloned and the expression of the IR gene in the retina was characterized. Preliminary reports of this study have been published previously in abstract form.8


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
RNA Isolation, RT-PCR, and Subcloning
The handling and treatment of all animals used in this study adhered to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Goldfish (4–6 in. standard length) were dark adapted to aid in isolating the retinas and killed by exsanguination. The retinas were dissected from the globes and immediately submerged in TRIzol Reagent (Gibco BRL, Gaithersburg, MD). Retinas were homogenized, and total RNA was isolated using the single-phase, phenol/guanidinium method described by the manufacturer. Similar methods were used to isolate total RNA from brain, gill, heart, skeletal muscle, kidney, and liver. Precipitated RNA was resuspended in RNase-free water and used immediately for the reverse transcription-polymerase chain reaction (RT-PCR) or resuspended in deionized formamide and stored at -80°C (for Northern analysis).

First-strand cDNA synthesis was performed using the Superscript Preamplification System (Gibco BRL) according to the manufacturer’s instructions. The PCR was performed in a total volume of 50 µl containing 2 µl of the RT reaction, 20 mM Tris-HCl, pH 8.4, 50 mM KCl, 1.5 mM MgCl2, 200 µM dNTPs, and 2.5 U Taq DNA polymerase. Degenerate oligonucleotide primers, reported previously to amplify insulin receptor cDNAs from the gill cartilage of coho salmon9 (primers IR-3 and IR-10), were used at a concentration of 100 ng/reaction. The PCR reaction was allowed to run for 30 cycles (95° for 30 seconds; 55° for 2 minutes; 72° for 2 minutes) followed by 72° for 10 minutes.

PCR products were separated on a 1% agarose gel, and a single band at approximately 1800 bp was purified and subcloned using pGEM-T vector (Promega, Madison, WI). Plasmid DNA was purified from multiple bacterial colonies, and the inserts were completely sequenced on both strands with overlapping runs by the DNA Sequencing Core at the University of Michigan. Raw sequence data were assembled using the Sequencing Project Manager software (DNA Star; Lasergene, Madison, WI). Open reading frames were identified and translated, and the nucleotide and deduced amino acid sequences were compared with previously published sequences (GenBank Database).

Northern Analysis
Blots of total RNA from several tissues were probed for the Northern blot analysis. Twenty micrograms of RNA was loaded in each lane, separated electrophoretically in an agarose gel, transferred to Hybond+ filters (Amersham Pharmacia Biotech, Amersham, United Kingdom) and photocross-linked (Stratalinker; Stratagene, La Jolla, CA). Blots were hybridized overnight at 42°C with random-primed, 32P-labeled probes (>1 x 108 cpm; rediPrime II; Amersham Pharmacia Biotech) and washed the next day in 2x SSC/0.5%SDS at room temperature for 30 minutes, followed by a wash in 0.1x SSC/0.5% SDS at 55°C for 30 minutes. Hybridization signal was detected by exposing the blots to a Storage Phosphor Screen (Molecular Dynamics, Sunnyvale, CA). Each blot was stripped with boiling 0.1x SSC/0.5% SDS and reprobed. Uniformity of loading was verified by ethidium staining of gels and/or staining membranes after transfer with methylene blue.

Tissue Processing and In Situ Hybridization
Briefly, eyecups were fixed for 1 to 2 hours in fresh 4% paraformaldehyde, in 100 mM phosphate buffer, pH 7.2, and immersed overnight at 4°C in 20% sucrose in phosphate-buffered saline (PBS). The next day eyecups were infiltrated in a solution containing a 2:1 ratio of 20% sucrose/PBS and O.C.T. Compound (Tissue-Tek; Sakura Finetek, Torrance, CA), embedded in 100% O.C.T., and frozen. Retinas were sectioned at 10 µm using a cryostat and mounted on TESPA-coated slides (Sigma, St. Louis, MO).

Plasmids containing gfIR-1 and gfIR-2 (see below) were linearized, and digoxygenin-labeled riboprobes (both sense and antisense) were synthesized by in vitro translation using a DIG-RNA labeling kit (Boehringer Mannheim GMbH, Mannheim, Germany). Without further processing of the riboprobes, in situ hybridizations were performed using methods published previously.10


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
RT-PCR using retinal RNA and degenerate oligonucleotide primers9 amplified cDNAs with homology to vertebrate sequences for both the IGF-1 and the IRs. (A description of the goldfish IGF-1 receptor will be reported elsewhere [Otteson DC, Cirenza PF, Hitchcock PF, unpublished results]; see Ref. 11 for a preliminary report.) Comparison of the nucleotide sequences showed that clones encoding the goldfish IR were partial cDNAs, which segregated into two groups that were 67.9% identical (data not shown). Clones in the first group, designated gfIR-1, were 1740 bp in length; clones in the second group, designated gfIR-2, were 1752 bp in length. The deduced amino acid sequences (Fig. 1) show that both gfIR-1 and gfIR-2 encode a portion of the extracellular {alpha}-domain, the transmembrane domain, and a portion of the intracellular ß-domain. In addition, both clones contain sequences common to all receptor tyrosine kinases, including conserved cysteine (C) and tyrosine (Y) residues, the tetrabasic proteolytic cleavage site (RRRR/RQRR), and the tyrosine kinase signature sequence (GxGxxG21xK).12 gfIR-1 and gfIR-2 share similar levels of identity when compared with equivalent sequences of IRs from humans and fish (salmon and turbot; Table 1 , Fig. 1 ). A pairwise comparison of amino acid sequences between gfIR-1 and -2 and cDNAs for the two goldfish IGF-1 receptors showed that the goldfish IR was more similar to IR homologues from other animals than to goldfish IGF-1R (Table 1) , consistent with the interpretation that gfIR-1 and -2 are distinct from the cDNAs encoding the IGF-1 receptor. Further, comparisons between gfIR-1 and -2 showed that they are only 69.7% identical (Fig. 1 and Table 1 ). We interpret this difference in sequence identity, at both the nucleotide and amino acid levels, to indicate that gfIR-1 and -2 transcripts represent two, nonallelic genes encoding the IR.



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  		Figure 1. Alignment of deduced amino acid sequences of IRs from goldfish, human, salmon, and turbot. Highlighted in bold are conserved tyrosine (Y) and cysteine (C) residues, the proteolytic cleavage site that separate the {alpha}- and ß-subunits of the insulin receptor (RRRR), and the signature sequence identifying the intracellular kinase domain (GxGxxG21xK). The putative transmembrane domain is underlined. GenBank Accession numbers: gfIR-1, AF218355; gfIR-2, AF321225; human IR, NM 000208/NM 000207; salmon (sir-1), AF021040; turbot IR, AJ224994.

 

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  		Table 1. Comparisons of Amino Acid Identity among gfIR-I and -2 and Insulin-Receptor Genes

 
The tissue distribution of IR transcripts was determined in Northern blots that were sequentially probed with gfIR-1 (Fig. 2A) and gfIR-2 (Fig. 2B) . Probes synthesized from gfIR-1 hybridize with a single transcript at approximately 11 kb. The expression of level the 11-kb transcript is highest in retina, lowest in muscle, and present in brain, gill, heart, kidney, and liver. In contrast, probes synthesized from gfIR-2 hybridized with a major transcript at approximately 7 kb. Similar to the high-molecular-weight transcript of gfIR-1, gfIR-2 expression is highest in the retina, lowest is in skeletal muscle, and present in brain, gill, heart, kidney, and liver.



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  		Figure 2. Northern blot analysis showing tissue expression of gfIR-1 and -2. (A and B) Expression patterns of gfIR-1 and gfIR-2, respectively. The apparent band at 4 kb is background hybridization to the 28S ribosomal RNA.

 
Figure 3 illustrates the cellular expression of gfIR-1 as revealed by in situ hybridization. Consistent with the high levels of expression of IR transcripts observed by Northern blot analysis, the IR appears to be expressed by most, if not all differentiated neurons (Fig. 3A) . Qualitatively, the expression appears to be highest for ganglion cells and lower, but uniform, among neurons in the inner and outer nuclear layers. gfIR-1 is also expressed by the retinal progenitors within the CGZ and cells of the adjacent unpigmented iris epithelium (Fig. 3B) . In situ hybridization with gfIR -2 yielded a pattern of hybridization similar to that for gfIR-1 (data not shown).



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  		Figure 3. In situ hybridization of gfIR-1 to retinal sections. (A) Cellular pattern of the IR expression within central (mature) retina. (B) IR expression within the circumferential germinal zone and unpigmented iris epithelium, which lies just to the right of the CGZ. (C) A section hybridized with the sense riboprobe as a negative control. Note the absence of any cellular hybridization. Scale bar, 50 µm. onl, outer nuclear layer; inl, inner nuclear layer; gcl, ganglion cell layer; CGZ, circumferential germinal zone.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Insulin is an evolutionarily ancient polypeptide that is the defining member of a family of related peptides that regulate proliferation and cellular metabolism, differentiation, and growth.13 14 15 16 24 25 The action of insulin is mediated by a high-affinity, receptor-tyrosine kinase that shares structural features with all receptor-tyrosine kinases12 and is most similar to the receptor for IGF-1.17 Although principally studied in mammalian systems, IRs are expressed in various fish tissues,18 including the brain19 and retina (see Results). Unlike mammals (and birds), however, insulin is not synthesized in the teleost brain,20 suggesting that insulin acting in the avascular retina of goldfish must be actively transported from the circulation.

Sequence comparisons of the partial cDNAs encoding the IRs in goldfish revealed that clones segregated into two groups that at the nucleotide level were only 67.9% identical. This relatively low degree of similarity cannot be attributed to amplification or sequencing errors and suggests that goldfish possess two genes encoding the IR. This was not unanticipated. Two distinct cDNAs encoding the goldfish IGF-1 receptor were isolated in parallel with the IR cDNAs,11 and multiple cDNAs encoding the IRs have been amplified from salmon tissues using the PCR primers described here.9 Multiple genes in fish are believed to reflect an ancient genome duplication event, perhaps as recently as 16 million years ago.21 The relatively low degree of identity between genes encoding the same protein is interpreted to show that once duplicated, each gene accumulates mutations independently.

Insulin (as well as IGF-1) is mitogenic for neuronal progenitors in the retinas of fish.1 22 Boucher and Hitchcock1 showed that both insulin and IGF-1 stimulate proliferation of cells in the CGZ; each peptide was potent at concentrations as low as 1 nM, and both produced a response similar in magnitude. Based on these observations, it was suggested that each peptide acts through its cognate receptor. The results from the in situ hybridizations (see Fig. 3B ) confirm this suggestion. Retinal progenitors within the CGZ contain mRNA encoding the IR and presumably express functional receptors. Insulin is a mitogen for retinal progenitors in embryonic birds,14 23 and the results of the present study suggest it may play a similar role regulating the persistent mitotic activity in the retinas of adult fish.

In addition to its mitogenic effects, insulin can have multiple other effects in the both the developing and mature nervous system.14 Insulin is best known as a regulator of glucose metabolism, and tight control of glucose utilization is perhaps the major function of this peptide in the nervous system.25 In addition, however, insulin can act as a trophic factor to promote neuronal differentiation, process outgrowth, and synapse formation.14 15 16 24 25 Further, insulin can modulate synaptic transmission. IRs are physically associated with postsynaptic specializations,26 and exogenous insulin alters the electrical response of neurons in the olfactory bulb27 and decreases the amplitude of the a- and b-waves of the bovine electroretinogram.28 Expression of the IR by the postmitotic cells in the retina of the goldfish suggests that among these cells insulin may have pliotropic effects, from regulating metabolism to modulating synaptic transmission.

Finally, the cellular expression of insulin and IGF-1 receptors in the goldfish’s retina appears to be completely overlapping11 ; differentiated retinal cells as well as the retinal progenitors express both receptors. This suggests that a significant fraction of the insulin and IGF-1 receptors in the fish retina may exist as hybrids, dimers of insulin and IGF-1 half-receptors. Hybrid receptors are widely distributed in mammalian tissues29 and are expressed in the embryonic retina of birds.30 Hybrid receptors bind IGF-1, but not insulin, with high affinity29 31 (although see Ref. 30 ) and may regulate a tissue’s sensitivity to insulin by sequestering some IRs in an inactive form.32 Hybrid receptors, if present, represent another level of complexity of insulin-regulated events in the teleost retina.


   Acknowledgements
 
The authors thank members of the Hitchcock laboratory and Robert Hausman for critically reading earlier versions of this article, Mitchell Gillett for technical assistance, and Dorothy Giebel for secretarial assistance.


   Footnotes
 
Supported by National Eye Institute Grant EY07060.

Submitted for publication March 21, 2001; revised April 18, 2001; accepted May 15, 2001.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Peter F. Hitchcock, Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, School of Medicine, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105. peterh{at}umich.edu


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  8. Hitchcock, P, Otteson, DC, Cirenza, PF (2000) Molecular cloning and cellular expression of the insulin receptor in the retina of the goldfish [ARVO Abstract] Invest Ophthalmol Vis Sci 40(4),S179Abstract nr 4504
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