Brian Perkins Lab | Lerner Research Institute

Principal Investigator

Brian Perkins, PhD

Staff
Email: [email protected]
Location: Cleveland Clinic Main Campus

Research

Inherited retinal degenerations (IRDs) are genetic diseases that lead to the progressive loss of photoreceptors and the permanent loss of vision. Wild-type zebrafish regenerate photoreceptors after acute injury by reprogramming Müller glia into stem-like cells that produce retinal progenitors. This regenerative process fails to occur in zebrafish models of IRDs. The goal of my lab is to address the critical unanswered question as to why retinal regeneration fails to occur in zebrafish mutants with photoreceptor degeneraiton and chronic inflammation. We have found that Notch pathway inhibition can promote photoreceptor regeneration in the zebrafish cep290 and bbs2 models of progressive degeneration and that immunosuppression prevents photoreceptor loss. These results offer insight into the pathways that promote Müller glia-dependent regeneration and the role of inflammation in photoreceptor degeneration. Our central hypothesis is that in zebrafish models of retinal degeneration, chronic inflammation results in elevated Notch and NF-kB signaling that restricts the regenerative response to acute injury. Evidence from the literature and our lab have rigorously demonstrated that Notch signaling in Müller glia differs in response to acute injury or chronic degeneration. Understanding the link between pro-inflammatory signaling from microglia and Notch signaling in Müller glia has not been previously addressed. Furthermore, our current understanding of how inflammatory cytokines signal through the NF-kB pathway has only been studied in the context of wild-type animals. The goal of the lab is to provide critical insight into the relationship between microglia and Müller glia regeneration in chronic disease. We use state-of-the-art sequencing technologies to identify Müller glia- and microglia-specific changes in gene expression in cep290 and bbs2 models in order to elucidate the relationship between inflammation and regeneration. We will also identify and test specific ligand-receptor pairs to identify the mechanisms that maintain Notch signaling in the zebrafish degeneration mutants and identify key factors that stimulate NF-kB signaling. Understanding the mechanisms that underpin retinal regeneration in multiple zebrafish disease models will generate novel hypotheses that can ultimately be translated into humans with retinal degenerative diseases.

Biography

I have been an active participant in vision research for over 25 years and have been continuously funded by the NIH for almost 20 years by R01 and R21 mechanisms. My laboratory uses zebrafish to investigate photoreceptor regeneration in models of inherited retinal disease. For 20 years I studied
several zebrafish mutants harboring mutations in genes required for cilia function and photoreceptor survival. My independent career started at Texas A&M, where I described early ciliogenesis defects in zebrafish ift mutants. Using a zebrafish model of choroideremia, my group was the first to demonstrate that defects in the RPE initiate and trigger photoreceptor degeneration. We elucidated the requirement for IFT57 within the IFT particle and discovered that retrograde trafficking by dynein-2 motors is essential for photoreceptor survival. After moving to the Cleveland Clinic, my group defined a novel role for the Wrb protein in ribbon synapse function and initiated a long-term interest in zebrafish models of ciliopathies. We described the phenotypes of zebrafish arl13b, ahi1, bbs2, and cep290 mutants and explored genetic interactions between these various genes. Recently, my group has switched our focus to understanding the mechanisms that regulate regeneration in diseased retina. My group discovered that genetic models of degeneration retain the capacity to regenerate, but require additional suppression of Notch signaling to stimulate Muller cell dedifferentiation and proliferation. Since starting my independent lab in 2004, I have trained 8 PhD students and 5 postdoctoral fellows, in addition to over 30 undergraduate students. Trainees from the laboratory have successfully moved into academia, biotech, law, and medicine. I am a strong advocate for trainees to attend scientific meetings to present their work and my goal is to encourage growth in scientific writing and critical thinking skills for trainees at all levels.

Education & Professional Highlights

Research

Cilia Biology

I spent over 12 years investigating the cellular mechanisms of cilia formation in zebrafish. Using photoreceptors as a model, we studied the effect of mutations in the Intraflagellar Transport (IFT) machinery, established a role for retrograde molecular motors in photoreceptor outer segment
formation, and used zebrafish as a model for human disease for genes such as ahi1, arl13b, and cep290. We discovered that cilia exhibit a highly symmetrical planar polarity in vertebrate photoreceptors. We also established that the ciliary gene arl13b genetically interacts with the planar
cell polarity gene vangl2. These studies have revealed new genetic pathways regulating cilia formation and provide novel insight into potential mechanisms of blindness.

a. Lessieur EM, Song P, Nivar GC, Piccillo EM, Fogerty J, Rozic R, Perkins BD. Ciliary genes
arl13b, ahi1 and cc2d2a differentially modify expression of visual acuity phenotypes but do not
enhance retinal degeneration due to mutation of cep290 in zebrafish. PLoS One.
2019;14(4):e0213960. PubMed Central PMCID: PMC6457629.

b. Lessieur EM, Fogerty J, Gaivin RJ, Song P, Perkins BD. The Ciliopathy Gene ahi1 Is Required for
Zebrafish Cone Photoreceptor Outer Segment Morphogenesis and Survival. Invest Ophthalmol
Vis Sci. 2017 Jan 1;58(1):448-460. PubMed Central PMCID: PMC5270624.

c. Song P, Dudinsky L, Fogerty J, Gaivin R, Perkins BD. Arl13b Interacts With Vangl2 to Regulate
Cilia and Photoreceptor Outer Segment Length in Zebrafish. Invest Ophthalmol Vis Sci. 2016 Aug
1;57(10):4517-26. PubMed Central PMCID: PMC5015978.

d. Krock BL, Perkins BD. The intraflagellar transport protein IFT57 is required for cilia maintenance
and regulates IFT-particle-kinesin-II dissociation in vertebrate photoreceptors. J Cell Sci. 2008 Jun
1;121(11):1907-15. PubMed Central PMCID: PMC2637114.

Retinal Regeneration

Although it is assumed that zebrafish regenerate retinal neurons following damage and disease, knowledge about regeneration comes primarily from studies where the retina was acutely damaged. However, multiple reports exist of progressive photoreceptor degeneration in adult zebrafish29-34. Our publications and preliminary data demonstrate that the zebrafish cep290 and bbs2 mutants undergo progressive photoreceptor degeneration, exhibit signs of inflammation and activated microglia, and yet MG fail to regenerate lost photoreceptors. Given the capacity of zebrafish to regenerate following damage, it is surprising that retinal degeneration occurs in these mutants. We have found that acute light damage triggers a regeneration response that partially restores cones. Inhibition of Notch signaling in uninjured cep290 or bbs2 mutants induced MG proliferation, indicating that the capacity for regeneration remains. We have also demonstrated that immunosuppression can
rescue cone survival in these mutants, potentially paving the way for novel therapeutic approaches to retinal disease.

a. Fogerty J, Song P, Boyd P, Grabinski SE, Hoang T, Reich A, Cianciolo LT, Blackshaw S, Mumm
JS, Hyde DR, Perkins BD. Notch Inhibition Promotes Regeneration and Immunosuppression
Supports Cone Survival in a Zebrafish Model of Inherited Retinal Dystrophy. J Neurosci. 2022 Jun
29;42(26):5144-5158. PubMed Central PMCID: PMC9236296.

b. Song P, Fogerty J, Cianciolo LT, Stupay R, Perkins BD. Cone Photoreceptor Degeneration and
Neuroinflammation in the Zebrafish Bardet-Biedl Syndrome 2 (bbs2) Mutant Does Not Lead to
Retinal Regeneration. Front Cell Dev Biol. 2020;8:578528. PubMed Central PMCID:
PMC7726229.

Zebrafish mutants affecting the visual system

In a screen for insertional mutations affecting visual function in zebrafish, we identified the zebrafish pinball wizard mutant, which exhibited photoreceptor degeneration and hearing loss. The mutation disrupts the wrb gene, which encodes a novel 170 amino acid protein with no known function. We found that wrb mutants exhibited mislocalization of ribbon synapse components, reduction in the number of docked ribbons at photoreceptor synapses, and significantly reduced ERG responses. Fewer contacts were seen between photoreceptors and bipolar cells in wrb-/- mutants. Wrb localized to the ER and synaptic region of photoreceptors. Morpholino knockdown of the cytosolic ATPase trc40, which targets TA proteins to the ER, also diminished the OKR. Overexpression of wrb fully restored contrast sensitivity in mutants, while overexpression of mutant wrbR73A, which cannot bind Trc40, did not. Thus, we identified a novel regulatory pathway of ribbon synapse formation in that Wrb and Trc40 are required for synaptic transmission between photoreceptors and bipolar cells, indicating that TA protein insertion by the TRC pathway is a critical step in ribbon synapse assembly and function.

a. Daniele LL, Emran F, Lobo GP, Gaivin RJ, Perkins BD. Mutation of wrb, a Component of the
Guided Entry of Tail-Anchored Protein Pathway, Disrupts Photoreceptor Synapse Structure and
Function. Invest Ophthalmol Vis Sci. 2016 Jun 1;57(7):2942-54. PubMed Central PMCID:
PMC4898200.

b. Gross JM, Perkins BD, Amsterdam A, Egaña A, Darland T, Matsui JI, Sciascia S, Hopkins N,
Dowling JE. Identification of zebrafish insertional mutants with defects in visual system
development and function. Genetics. 2005 May;170(1):245-61. PubMed Central PMCID:
PMC1444939.

Our Team

Publications

Selected Publications

View publications for Brian Perkins, PhD
(Disclaimer: This search is powered by PubMed, a service of the U.S. National Library of Medicine. PubMed is a third-party website with no affiliation with Cleveland Clinic.)

Wang J, Thomas HR, Thompson RG, Waldrep SC, Fogerty J, Song P, Li Z, Ma Y, Santra P, Hoover JD, Yeo NC, Drummond IA, Yoder BK, Amack JD, Perkins B, Parant JM. Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants. Dis Model Mech. 2022 Dec 1;15(12). doi: 10.1242/dmm.049568. Epub 2022 Dec 19. PubMed PMID: 36533556; PubMed Central PMCID: PMC9844136.

Fogerty J, Song P, Boyd P, Grabinski SE, Hoang T, Reich A, Cianciolo LT, Blackshaw S, Mumm JS, Hyde DR, Perkins BD. Notch Inhibition Promotes Regeneration and Immunosuppression Supports Cone Survival in a Zebrafish Model of Inherited Retinal Dystrophy. J Neurosci. 2022 Jun 29;42(26):5144-5158. doi: 10.1523/JNEUROSCI.0244-22.2022. Epub 2022 Jun 7. PubMed PMID: 35672150; PubMed Central PMCID: PMC9236296.

Banerjee S, Ranspach LE, Luo X, Cianciolo LT, Fogerty J, Perkins BD, Thummel R. Vision and sensorimotor defects associated with loss of Vps11 function in a zebrafish model of genetic leukoencephalopathy. Sci Rep. 2022 Mar 3;12(1):3511. doi: 10.1038/s41598-022-07448-1. PubMed PMID: 35241734; PubMed Central PMCID: PMC8894412.

Perkins BD. Zebrafish models of inherited retinal dystrophies. J Transl Genet Genom. 2022;6(1):95-110. doi: 10.20517/jtgg.2021.47. Epub 2022 Feb 8. PubMed PMID: 35693295; PubMed Central PMCID: PMC9186516.

Gulluni F, Prever L, Li H, Krafcikova P, Corrado I, Lo WT, Margaria JP, Chen A, De Santis MC, Cnudde SJ, Fogerty J, Yuan A, Massarotti A, Sarijalo NT, Vadas O, Williams RL, Thelen M, Powell DR, Schueler M, Wiesener MS, Balla T, Baris HN, Tiosano D, McDermott BM Jr, Perkins BD, Ghigo A, Martini M, Haucke V, Boura E, Merlo GR, Buchner DA, Hirsch E. PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation. Science. 2021 Dec 10;374(6573):eabk0410. doi: 10.1126/science.abk0410. Epub 2021 Dec 10. PubMed PMID: 34882480; PubMed Central PMCID: PMC7612254.

Song P, Fogerty J, Cianciolo LT, Stupay R, Perkins BD. Cone Photoreceptor Degeneration and Neuroinflammation in the Zebrafish Bardet-Biedl Syndrome 2 (bbs2) Mutant Does Not Lead to Retinal Regeneration. Front Cell Dev Biol. 2020;8:578528. doi: 10.3389/fcell.2020.578528. eCollection 2020. PubMed PMID: 33324636; PubMed Central PMCID: PMC7726229.

Pollock LM, Perkins B, Anand-Apte B. Primary cilia are present on endothelial cells of the hyaloid vasculature but are not required for the development of the blood-retinal barrier. PLoS One. 2020;15(7):e0225351. doi: 10.1371/journal.pone.0225351. eCollection 2020. PubMed PMID: 32735563; PubMed Central PMCID: PMC7394433.

Solanki AK, Kondkar AA, Fogerty J, Su Y, Kim SH, Lipschutz JH, Nihalani D, Perkins BD, Lobo GP. A Functional Binding Domain in the Rbpr2 Receptor Is Required for Vitamin A Transport, Ocular Retinoid Homeostasis, and Photoreceptor Cell Survival in Zebrafish. Cells. 2020 Apr 29;9(5). doi: 10.3390/cells9051099. PubMed PMID: 32365517; PubMed Central PMCID: PMC7290320.

Fogerty J, Stepanyan R, Cianciolo LT, Tooke BP, Perkins BD. Genomic non-redundancy of the mir-183/96/182 cluster and its requirement for hair cell maintenance. Sci Rep. 2019 Jul 16;9(1):10302. doi: 10.1038/s41598-019-46593-y. PubMed PMID: 31311951; PubMed Central PMCID: PMC6635406.

Lessieur EM, Song P, Nivar GC, Piccillo EM, Fogerty J, Rozic R, Perkins BD. Ciliary genes arl13b, ahi1 and cc2d2a differentially modify expression of visual acuity phenotypes but do not enhance retinal degeneration due to mutation of cep290 in zebrafish. PLoS One. 2019;14(4):e0213960. doi: 10.1371/journal.pone.0213960. eCollection 2019. PubMed PMID: 30970040; PubMed Central PMCID: PMC6457629.

Lessieur EM, Fogerty J, Gaivin RJ, Song P, Perkins BD. The Ciliopathy Gene ahi1 Is Required for Zebrafish Cone Photoreceptor Outer Segment Morphogenesis and Survival. Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):448-460. doi: 10.1167/iovs.16-20326. PubMed PMID: 28118669; PubMed Central PMCID: PMC5270624.

Zhu L, Chen L, Yan L, Perkins BD, Li S, Li B, Xu HA, Li XJ. Mutant Ahi1 Affects Retinal Axon Projection in Zebrafish via Toxic Gain of Function. Front Cell Neurosci. 2019;13:81. doi: 10.3389/fncel.2019.00081. eCollection 2019. PubMed PMID: 30949029; PubMed Central PMCID: PMC6438259.

Miller AH, Howe HB, Krause BM, Friedle SA, Banks MI, Perkins BD, Wolman MA. Pregnancy-Associated Plasma Protein-aa Regulates Photoreceptor Synaptic Development to Mediate Visually Guided Behavior. J Neurosci. 2018 May 30;38(22):5220-5236. doi: 10.1523/JNEUROSCI.0061-18.2018. Epub 2018 May 8. PubMed PMID: 29739870; PubMed Central PMCID: PMC5977450.

Bell BA, Yuan A, Dicicco RM, Fogerty J, Lessieur EM, Perkins BD. The adult zebrafish retina: In vivo optical sectioning with Confocal Scanning Laser Ophthalmoscopy and Spectral-Domain Optical Coherence Tomography. Exp Eye Res. 2016 Dec;153:65-78. doi: 10.1016/j.exer.2016.10.001. Epub 2016 Oct 6. PubMed PMID: 27720860; PubMed Central PMCID: PMC5120996.

Song P, Dudinsky L, Fogerty J, Gaivin R, Perkins BD. Arl13b Interacts With Vangl2 to Regulate Cilia and Photoreceptor Outer Segment Length in Zebrafish. Invest Ophthalmol Vis Sci. 2016 Aug 1;57(10):4517-26. doi: 10.1167/iovs.16-19898. PubMed PMID: 27571019; PubMed Central PMCID: PMC5015978.

Daniele LL, Emran F, Lobo GP, Gaivin RJ, Perkins BD. Mutation of wrb, a Component of the Guided Entry of Tail-Anchored Protein Pathway, Disrupts Photoreceptor Synapse Structure and Function. Invest Ophthalmol Vis Sci. 2016 Jun 1;57(7):2942-54. doi: 10.1167/iovs.15-18996. PubMed PMID: 27273592; PubMed Central PMCID: PMC4898200.

Fogerty J, Denton K, Perkins BD. Mutations in the Dynein1 Complex are Permissible for Basal Body Migration in Photoreceptors but Alter Rab6 Localization. Adv Exp Med Biol. 2016;854:209-15. doi: 10.1007/978-3-319-17121-0_28. PubMed PMID: 26427413; PubMed Central PMCID: PMC4939795.

Babino D, Perkins BD, Kindermann A, Oberhauser V, von Lintig J. The role of 11-cis-retinyl esters in vertebrate cone vision. FASEB J. 2015 Jan;29(1):216-26. doi: 10.1096/fj.14-261693. Epub 2014 Oct 17. PubMed PMID: 25326538; PubMed Central PMCID: PMC4285540.

DiCicco RM, Bell BA, Kaul C, Hollyfield JG, Anand-Apte B, Perkins BD, Tao YK, Yuan A. Retinal regeneration following OCT-guided laser injury in zebrafish. Invest Ophthalmol Vis Sci. 2014 Sep 9;55(10):6281-8. doi: 10.1167/iovs.14-14724. PubMed PMID: 25205862; PubMed Central PMCID: PMC4191177.

Krock BL, Perkins BD. The Par-PrkC polarity complex is required for cilia growth in zebrafish photoreceptors. PLoS One. 2014;9(8):e104661. doi: 10.1371/journal.pone.0104661. eCollection 2014. PubMed PMID: 25144710; PubMed Central PMCID: PMC4140697.

Wasfy MM, Matsui JI, Miller J, Dowling JE, Perkins BD. myosin 7aa(-/-) mutant zebrafish show mild photoreceptor degeneration and reduced electroretinographic responses. Exp Eye Res. 2014 May;122:65-76. doi: 10.1016/j.exer.2014.03.007. Epub 2014 Apr 1. PubMed PMID: 24698764; PubMed Central PMCID: PMC4034177.

Ramsey M, Perkins BD. Basal bodies exhibit polarized positioning in zebrafish cone photoreceptors. J Comp Neurol. 2013 Jun 1;521(8):1803-16. doi: 10.1002/cne.23260. PubMed PMID: 23171982; PubMed Central PMCID: PMC3594345.

Careers

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