Orkun Akin, Ph.D.

Research interest: 

What makes brains and neurons so compelling to look at is their astonishingly intricate organization. The grand challenge of developmental neurobiology is to understand how the information in the genome is used to build such a stereotyped, complex structure. This challenge has been taken up in many model organisms and for different stages of neuronal development: profileration, differentiation, axon guidance, and synapse formation. In the fruit fly, the workhorse of classic genetic analysis, we discovered a new epoch in brain development that was previously unknown for invertebrate biology. Using 2-photon imaging, we found that soon after most axon guidance events are completed and co-incident with the onset of synapse formation, neurons in the developing brain begin to show coordinated, periodic bursts of electrical activity. In the visual system, this activity is independent of sensory stimulation (i.e. the fly cannot see yet), lasts for two days until the adult emerges from its pupa, and is cell-type specific. That is, the pattern of activity is distinct for each defined cell type but similar for neurons that are synaptic partners in the adult. Notably, stimulus-independent neuronal activity in the developing vertebrate brain has been observed and studied in the past three decades; the discovery of a comparable phenomenon in an invertebrate suggests that this is a general feature of the assembly of complex brains. We are now asking where the activity is coming from, how it is organized and coordinated across the brain, and how it is contributing to brain development. The remarkable toolkit available in the fly visual system, from the complete connectome to the ability to monitor and manipulate individual neurons, provides an extraordinary opportunity address these questions.

David S. Williams, Ph.D.

Research

Dr. Williams’ laboratory focuses on the cell biology of photoreceptor and RPE cells. His group is especially interested in cell biological studies of the retina in relation to retinal function and inherited retinal disease. Basic science investigations in the laboratory include identifying how proteins and organelles are transported and targeted within the photoreceptor and RPE cells. The identification of roles of different motor proteins has advanced the molecular understanding of cellular events, such as disk membrane renewal and associated retinal disease. The laboratory is also interested in the translation of basic science of the retina to clinical research. Basic studies on myosin VIIa, an unconventional actin-based motor protein, have enabled the establishment of assays for use in preclinical studies on gene therapy for a type of Usher syndrome, an inherited eye disorder that involves both deafness and retinal degeneration. Studies with mutant mice have also led to the development of useful models for retinal degeneration, including age-related macular degeneration.

Publications

Hazim RA, Paniagua AE, Tang L, Yang K, Kim KKO, Stiles L, Divakaruni AS, Williams DS: Vitamin B3, nicotinamide, enhances mitochondrial metabolism to promote differentiation of the retinal pigment epithelium. Journal of Biological Chemistry 298:102286, 2022.

https://www.ncbi.nlm.nih.gov/pubmed/35868562             PMID: 35868562            doi: 10.1016/j.jbc.2022.102286

 

Chadha A, Paniagua AE, Williams DS:  Comparison of ciliary targeting of two rhodopsin-like GPCRs: role of C-terminal localization sequences in relation to cilium type.  Journal of Neuroscience, 41:7514-7531, 2021.

https://www.ncbi.nlm.nih.gov/pubmed/34301828             doi.org/10.1523/JNEUROSCI.0357-21.2021

 

Hultgren NW, Fang JS, Ziegler ME, Ramirez RN, Phan DTT, Hatch MMS, Welch-Reardon KM, Paniagua AE, Kim LS, Shon NN, Williams DS, Mortazavi A, and Hughes CCW: Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis. Nature Communications, 11:5400, 2020.

PMID: 33106502  PMCID: PMC7588439  DOI: 10.1038/s41467-020-18633-z

 

Jiang M, Paniagua AE, Volland S, Wang H, Balaji A, Li DG, Lopes VS, Burgess BL, Williams DS: Microtubule motor transport in the delivery of melanosomes to the actin-rich apical domain of the retinal pigment epithelium. Journal of Cell Science, 133 (15): jcs242214, 2020.

PMID: 32661088  PMCID: PMC7420818  DOI: 10.1242/jcs.242214

 

Lakkaraju A, Umapathy A, Tan LX, Daniele L, Philp NJ, Boesze-Battaglia K, Williams DS: The cell biology of the retinal pigment epithelium. Progress in Retina and Eye Research, 78:100846, 2020.

PMID: 32105772  PMCID:              DOI: 10.1016/j.preteyeres.2020.100846

 

Milstein ML, Cavanaugh B, Roussey NM, Volland S, Williams DS, Goldberg AFX: Multistep peripherin-2/rds self-assembly drives membrane curvature for outer segment disk architecture and photoreceptor viability. Proceedings of the National Academy of Sciences, 117:4400-4410, 2020.

PMID: 32041874  PMCID: PMC7049111  DOI: 10.1073/pnas.1912513117 

 

Chadha A, Volland S, Baliaouri NV, Tran EM, Williams DS: The route of the visual receptor rhodopsin along the cilium. Journal of Cell Science, 132(10):jcs229526, 2019.

PMID: 30975916  PMCID: PMC6550008  DOI: 10.1242/jcs.229526
Esteve-Rudd J, Hazim RA, Diemer T, Paniagua AE, Volland S, Umapathy A, Williams DS: Defective phagosome motility and degradation in cell non-autonomous RPE pathogenesis of a dominant macular degeneration. Proceedings of the National Academy of Sciences, 115:5468-5473, 2018.

PMID: 29735674  PMCID: PMC6003516  DOI: 10.1073/pnas.1709211115

Volland S, Hughes LC, Kong C, Burgess BL, Linberg KA, Luna G, Zhou ZH, Fisher SK, and Williams DS: Three-dimensional organization of nascent rod outer segment disk membranes. Proceedings of the National Academy of Sciences, 112(48):14870-14875, 2015.

PMID: 26578801  PMCID: PMC4672767  DOI: 10.1073/pnas.1516309112

 

Jiang M, Esteve-Rudd J, Lopes VS, Diemer T, Lillo C, Rump A, Williams DS: Microtubule motors transport phagosomes in the RPE and lack of KLC1 leads to AMD-like pathogenesis. Journal of Cell Biology, 210(4):595-611, 2015.

PMID: 26261180  PMCID: PMC4539993  DOI: 10.1083/jcb.201410112

 

Lopes VS, Boye SE, Louie CM, Boye S, Dyka F, Chiodo V, Fofo H, Hauswirth WW, Williams DS:  Retinal gene therapy with a large MYO7A cDNA using Adeno-associated virus.  Gene Therapy 20:824-833 2013.

http://www.ncbi.nlm.nih.gov/pubmed/23344065

 

Trivedi D, Colin E, Louie CM, Williams DS:  Live-cell imaging evidence for the ciliary transport of rod photoreceptor opsin by heterotrimeric kinesin-2.  Journal of Neuroscience 32:10587-10593, 2012.

http://www.ncbi.nlm.nih.gov/pubmed/22855808

 

Louie CM, Caridi G, Lopes VS, Brancati F, Kispert A, Lancaster MA, Schlossman AM, Otto EA, Leitges M, Grone HJ, Lopez I, Gudiseva HV, O’Toole JF, Vallespin E, Ayyagari R, Ayuso C, Cremers FP, den Hollander AI, Koenekoop RK, Dallapiccola B, Ghiggeri GM, Hildebrandt F, Valente EM, Williams DS, Gleeson JG:  AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis.  Nature Genetics 42:175-180, 2010.

http://www.ncbi.nlm.nih.gov/pubmed/20081859

Schwander M, Lopes V, Sczaniecka A, Gibbs D, Lillo C, Delano D, Tarantino LM, Wiltshire T, Williams DS, Müller U:  A novel allele of myosin VIIa reveals a critical function for the C-terminal FERM domain for melanosome transport in retinal pigment epithelial cells Journal of Neuroscience 29:15810-15818, 2009.

http://www.ncbi.nlm.nih.gov/pubmed/20016096

 

Williams DS, Cash A, Hamadani L, Diemer T: Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway. Aging Cell, 8:765-768, 2009.

http://www.ncbi.nlm.nih.gov/pubmed/19793063

 

Yang Z*, Chen Y, Lillo C, Chien J, Yu Z, Michaelides M, Klein M, Howes KA, Li Y, Kaminoh Y, Chen H, Zhao C, Al-Sheikh YT, Karan G, Corbeil D, Escher P, Kamaya S, Li C, Johnson S, Frederick JM, Zhao Y, Wang C, Cameron DJ, Huttner WB, Schorderet DF, Munier FL, Moore AT, Birch DG, Baehr W, Hunt DM, Williams DS*, Zhang, K*:  Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice. Journal of Clinical Investigation 118:2908-2916, 2008. *Co-corresponding authors.

http://www.ncbi.nlm.nih.gov/pubmed/18654668

 

Hashimoto T, Gibbs D, Lillo C, Azarian SM, Legacki E, Zhang X-M, Yang XJ, Williams DS:  Lentiviral gene replacement therapy of retinas in a mouse model for Usher sydrome type 1B. Gene Therapy 14:584-594, 2007.

http://www.ncbi.nlm.nih.gov/pubmed/17268537

 

Schubert D, Williams D:  ‘Cisgenic’ as a product designation.  Nature Biotechnology 24:7-9, 2006.

http://www.ncbi.nlm.nih.gov/pubmed/17093469

 

Stokin GB, Lillo C, Falzone T, Brusch RG, Rockenstein E, Mount S, Raman R, Davies P, Masliah E, Williams DS, Goldstein LSB:  Axonpathy and transport deficits in the pathogenesis of Alzheimer’s disease.  Science 307:1282-1288, 2005.

http://www.ncbi.nlm.nih.gov/pubmed/15731448

 

Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, Muerb U, O’Toole JF, Helou J, Attanasio M, Utsch B, Sayer JA, Lillo C, Jimeno D, Couck P, De Paepe A, Reinhardt R, Klages S, Ysuda M, Kawakami I, Kusakabe T, Omran H, ImmA, Tippens M, Raymond PA, Hill J, Beales P, He S, Kispert A, Margolis B, Williams DS, Swaroop A, Hildebrandt F:  A novel ciliary IQ domain protein, NPHP5, is mutated in Senior-Loken syndrome (Nephronophthisis with retinitis pigmentosa), and interacts with RPGR and calmodulin.  Nature Genetics 37:282-288, 2005.

http://www.ncbi.nlm.nih.gov/pubmed/15723066

 

Karan G, Lillo C, Yang Z, Cameron J, Locke KG, Zhao Y, Thirumalaichary S, Li C, Birch DG, Vollmer-Sanar H, Williams DS*, Zhang K*: Lipofuscin accumulation, abnormal electrophysiology and photoreceptor degeneration in mutant ELOVL4 transgenic mice:  a model for macular degeneration Proceedings of the National Academy Sciences 102:4164-4169, 2005.  *Co-corresponding authors.

http://www.ncbi.nlm.nih.gov/pubmed/15749821

 

Gibbs D, Azarian SA, Lillo C, Klomp AEM, Kitamoto J, Steel KP, Libby RT, Williams DS: Role of myosin VIIa and Rab27a in the motility and localization of RPE melanosomes.  Journal of Cell Science 117:6473-6483, 2004.

http://www.ncbi.nlm.nih.gov/pubmed/15572405

 

Liu J, Lillo C, Jonsson PA, Ward CM, Subramaniam JR, Rothstein JD, Marklund S, Andersen PM, Brännström T, Wong PC, Williams DS, Cleveland DW:  Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria.  Neuron 43:5-17, 2004.

http://www.ncbi.nlm.nih.gov/pubmed/15233913

 

Siemens J, Lillo C, Dumont RA, Williams DS, Gillespie PG, Müller U: Cadherin 23 is a component of the tip link in hair cell stereocilia.  Nature 428:950-955, 2004.

http://www.ncbi.nlm.nih.gov/pubmed/15057245

 

Gibbs D, Kitamoto J, Williams DS: Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein. Proceedings National Academy Sciences, 100:6481-6486, 2003.

http://www.ncbi.nlm.nih.gov/pubmed/12743369

 

Marszalek JR, Liu X, Roberts E, Chui D, Marth J, Williams DS, Goldstein LSB:  Genetic evidence for a kinesin-II mediated pathway for opsin and arrestin transport in mammalian photoreceptors.  Cell 102:175-187, 2000.

http://www.ncbi.nlm.nih.gov/pubmed/10943838

 

Liu X, Udovichenko, IP, Brown SDM, Steel KP, Williams DS:  Myosin VIIa participates in opsin transport through the photoreceptor cilium.  Journal of Neuroscience 19:6267-6274, 1999.

http://www.ncbi.nlm.nih.gov/pubmed/10414956

 

Liu X, Ondek B, Williams DS:  Mutant myosin VIIa causes defective melanosome distribution in the RPE of shaker-1 mice.  Nature Genetics 19:117-118, 1998.

http://www.ncbi.nlm.nih.gov/pubmed/9620764

 

Arikawa K, Molday LL, Molday RS, Williams DS:  Localization of peripherin/rds in the disk membranes of cone and rod photoreceptors: relationship to disk membrane morphogenesis and retinal degeneration.  Journal of Cell Biology 116:659-667, 1992.

http://www.ncbi.nlm.nih.gov/pubmed/1730772     PMCID: PMC2289304   DOI: 10.1083/jcb.116.3.659

 

Arikawa K, Hicks JL, Williams DS:  Identification of actin filaments in the rhabdomeral microvilli of Drosophila photoreceptors. Journal of Cell Biology 110:1993-1998, 1990.

http://www.ncbi.nlm.nih.gov/pubmed/2112548     PMCID: PMC2116135    DOI: 10.1083/jcb.110.6.1993

 

Williams DS: Photoreceptor membrane shedding and assembly can be initiated locally within an insect eye.  Science 218:898-900 (plus front cover), 1982.

http://www.ncbi.nlm.nih.gov/pubmed/7134980                 DOI: 10.1126/science.7134980

 

Williams DS, McIntyre P: The principal eyes of a jumping spider have a telephoto component.  Nature 288:578-580, 1980.

http://www.www.nature.com/nature/journal/v288/n5791/abs/288578a0.html           doi.org/10.1038/288578a0

 

 

 

 

Anne Churchland, Ph.D.

Academic Titles/Accomplishments/Affiliations:

Professor of Neurobiology

Research interest:

* Multisensory behavior in rats and humans

* Measure and manipulate neural responses

* Analyses to understand population-level responses