Browsing by Author "Starost, Matthew F."

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    Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice
    (Elsevier, 2021) Kar, Rajesh Kumar; Hanner, Ashleigh S.; Starost, Matthew F.; Springer, Danielle; Mastracci, Teresa L.; Mirmira, Raghavendra G.; Park, Myung Hee; Biology, School of Science
    Eukaryotic initiation factor 5A (eIF5A)†, ‡ is an essential protein that requires a unique amino acid, hypusine, for its activity. Hypusine is formed exclusively in eIF5A post-translationally via two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase. Each of the genes encoding these proteins, Eif5a, Dhps, and Dohh, is required for mouse embryonic development. Variants in EIF5A or DHPS were recently identified as the genetic basis underlying certain rare neurodevelopmental disorders in humans. To investigate the roles of eIF5A and DHPS in brain development, we generated four conditional KO mouse strains using the Emx1-Cre or Camk2a-Cre strains and examined the effects of temporal- and region-specific deletion of Eif5a or Dhps. The conditional deletion of Dhps or Eif5a by Emx1 promotor–driven Cre expression (E9.5, in the cortex and hippocampus) led to gross defects in forebrain development, reduced growth, and premature death. On the other hand, the conditional deletion of Dhps or Eif5a by Camk2a promoter–driven Cre expression (postnatal, mainly in the CA1 region of the hippocampus) did not lead to global developmental defects; rather, these KO animals exhibited severe impairment in spatial learning, contextual learning, and memory when subjected to the Morris water maze and a contextual learning test. In both models, the Dhps-KO mice displayed more severe impairment than their Eif5a-KO counterparts. The observed defects in the brain, global development, or cognitive functions most likely result from translation errors due to a deficiency in active, hypusinated eIF5A. Our study underscores the important roles of eIF5A and DHPS in neurodevelopment.
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    Taperin bundles F-actin at stereocilia pivot points enabling optimal lifelong mechanosensitivity
    (Rockefeller University Press, 2025) Belyantseva, Inna A.; Liu, Chang; Dragich, Abigail K.; Miyoshi, Takushi; Inagaki, Sayaka; Imtiaz, Ayesha; Tona, Risa; Zuluaga-Osorio, Karen Sofia; Hadi, Shadan; Wilson, Elizabeth; Morozko, Eva; Olszewski, Rafal; Yousaf, Rizwan; Sokolova, Yuliya; Riordan, Gavin P.; Aston, S. Andrew; Rehman, Atteeq U.; Fenollar Ferrer, Cristina; Wisniewski, Jan; Gu, Shoujun; Nayak, Gowri; Goodyear, Richard J.; Li, Jinan; Krey, Jocelyn F.; Wafa, Talah; Faridi, Rabia; Adadey, Samuel Mawuli; Drummond, Meghan; Perrin, Benjamin; Winkler, Dennis C.; Starost, Matthew F.; Cheng, Hui; Fitzgerald, Tracy; Richardson, Guy P.; Dong, Lijin; Barr-Gillespie, Peter G.; Hoa, Michael; Frolenkov, Gregory I.; Friedman, Thomas B.; Zhao, Bo; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Stereocilia are rod-like mechanosensory projections consisting of unidirectionally oriented actin filaments that extend into the inner ear hair cell cytoskeleton, forming dense rootlets. Taperin (TPRN) localizes to the narrowed-down base of stereocilia, where they pivot in response to sound and gravity. We show that TPRN-deficient mice have progressive deafness characterized by gradual asynchronous retraction and fusion of outer and inner hair cell stereocilia, followed by synaptic abnormalities. Stereocilia that lack TPRN develop warped rootlets with gradual loss of TRIOBP-5 and ANKRD24 from mechanosensory rows starting postnatally. In contrast, TPRN overexpression causes excessive F-actin bundling, extra rows, and over-elongation of stereocilia during development. Purified full-length mouse TPRN cross-links F-actin into bendable bundles reflecting in vivo data. This F-actin-bundling ability is attributed to the TPRN N-terminal region. TPRN interacts with the membrane receptor PTPRQ, connecting the F-actin core to the plasma membrane, stabilizing stereocilia. Thus, TPRN is a specialized F-actin bundler strategically located to augment stereocilia rootlet formation and their pivot point flexibility for sustained sound-induced deflections.