Michael Robichaux, PhD

Research Interests

The Robichaux lab aims to discover how vision begins in our eyes on a molecular level. We apply these new molecular discoveries toward understanding the pathology of eye diseases that cause blindness. Our goal is to utilize these discoveries to learn how these devastating eye diseases can be treated and how vision can be rescued.

The retina is the neural tissue at the back of the eye. Photoreceptors, rods and cones, are specialized neurons of the retina that express opsin G-protein coupled receptors that absorb photons and initiate visual signaling. Rhodopsin is the opsin protein in rod photoreceptor neurons, and it is densely packaged into the distinctive layers of stacked membrane discs in a region of rods known as the outer segment. Based on the continuous renewal of outer segment discs, a unidirectional flow of newly synthesized material must be continuously trafficking through the biosynthetic inner segment region of rods and into many unique ciliary structures in rod neurons. Among these unique structures is a 300 nm thin connecting cilium and a pair of centrioles that comprise the subcellular domain known as the basal body. We are interested in discovering the mechanisms that regulate the cellular trafficking of rhodopsin and other proteins within the inner segment and ciliary structures of rod photoreceptors.

In many eye diseases, retinal neurodegeneration is caused by the mistrafficking of rhodopsin in rods, which leads to a disruption of rod neuron homeostasis, photoreceptor neuronal cell death and, eventually, blindness. Because all rhodopsin molecules are unidirectionally trafficked to the outer segment cilium in rods, a complex inner segment secretory system that is linked to cilia-associated proteins is integral to all rod trafficking events. This secretory-ciliary integration, along with the unique structures and morphology of rod neurons, makes the rod photoreceptor cell biology a unique and highly specialized subject of research.

Our interest in rhodopsin and the rod cilium is highly relevant to retinitis pigmentosa, which is a retinal neurodegenerative disease that affects 1 in 4,000 individuals in the United States (Hamel, 2006) and is the most prevalent human inherited retinal disease (Daiger et al., 2013). Among the approximately 150 genes linked to retinitis pigmentosa, inherited mutations of rhodopsin are the leading cause of the autosomal dominant form of retinitis pigmentosa (adRP) (Athanasiou et al, 2018). One rhodopsin mutation alone, the P23H point mutation, accounts for 10% of all adRP cases (Sullivan et al., 2006).

The Robichaux lab studies the complex biology of rhodopsin trafficking in rod neurons using advanced forms of microscopy to visualize molecular events in single rod neurons of the mouse retina. Among these microscopies is stochastic optical reconstruction microscopy (STORM), a form of super-resolution fluorescence microscopy. For our research projects, STORM is used in combination with electron microscopy, expansion microscopy and other modes of super-resolution microscopy, along with protein biochemistry and tissue culture applications.

STORM reconstruction of the ER in RPE1 cells expressing the fusion protein: Sec61b-SNAP.

Robichaux lab research projects include:

• A comprehensive localization analysis of the rod photoreceptor inner segment applying super-resolution techniques to map how rhodopsin is localized within the secretory system and cilia of rod neurons.
• A functional and morphological determination of how mislocalized mutant P23H-rhodopsin affects rod neurons and causes retinitis pigmentosa subcellular phenotypes.

References:

Hamel, C. (2006). Retinitis pigmentosa. Orphanet Journal of Rare Diseases, 1(1), 1–12. https://doi.org/10.1186/1750-1172-1-40

Daiger, S. P., Sullivan, L. S., & Bowne, S. J. (2013). Genes and mutations causing retinitis pigmentosa. Clinical Genetics, 84(2), 132–141. https://doi.org/10.1111/cge.12203

Athanasiou, D., Aguila, M., Bellingham, J., Li, W., McCulley, C., Reeves, P. J., & Cheetham, M. E. (2018). The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy. Progress in Retinal and Eye Research, 62, 1–23. https://doi.org/10.1016/j.preteyeres.2017.10.002

Sullivan, L. S., Bowne, S. J., Birch, D. G., Hughbanks-Wheaton, D., Heckenlively, J. R., Lewis, R. A., … Daiger, S. P. (2006). Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: A screen of known genes in 200 families. Investigative Ophthalmology and Visual Science, 47(7), 3052–3064. https://doi.org/10.1167/iovs.05-1443

Publications

Haggerty KN, Eshelman SC, Sexton LA, Frimpong E, Rogers LM, Agosto MA, Robichaux M.A. Super-resolution mapping in rod photoreceptors identifies rhodopsin trafficking through the inner segment plasma membrane as an essential subcellular pathway. PLoS Biol. 2024 Jan 8;22(1):e3002467. doi: 10.1371/journal.pbio.3002467. PMID: 38190419; PMCID: PMC10773939.

Albrecht, N. E., Jiang, D., Akhanov, V., Hobson, R., Speer, C. M., Robichaux, M. A., & Samuel, M. A. (2022). Rapid 3D-STORM imaging of diverse molecular targets in tissue. Cell reports methods, 2(7), 100253. https://doi.org/10.1016/j.crmeth.2022.100253. PMID: 35880013; PMCID: PMC9308169

Robichaux M.A., Nguyen V., Chan F., Kailasam L., He F., Wilson J.H., Wensel T.G. (2022). Subcellular localization of mutant P23H rhodopsin in an RFP fusion knock-in mouse model of retinitis pigmentosa. Dis Model Mech. May 1;15(5):dmm049336. doi: 10.1242/dmm.049336. Epub 2022 May 6. PMID: 35275162; PMCID: PMC9092655.

Potter, V. L., Moye, A. R., Robichaux, M. A., & Wensel, T. G. (2021). Super-resolution microscopy reveals photoreceptor-specific subciliary location and function of ciliopathy-associated protein CEP290. JCI Insight, 6(20). PMID: 34520396; PMCID: PMC8564900

Wensel, T.G., Potter, V.L., Moye, A., Zhang, Z., & Robichaux, M.A. (2021). Structure and dynamics of photoreceptor sensory cilia. Pflügers Archiv - European Journal of Physiology, doi.org/10.1007/s00424-021-02564-9. PMID: 34050409

Robichaux, M.A., Potter, V.L., Zhang, Z., He, F., Liu, J., Schmid, M.F., Wensel, T.G. (2019). Defining the Layers of a Sensory Cilium with STORM and Cryo-Electron Nanoscopy. Proceedings of the National Academy of Sciences. 116, 23562–23572 (2019). PMID: 31690665

For a full publication list, please visit: Publication Link