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Actin Is Required for Cytoskeletal Maintenance but Not Development

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Actin Is Required for Cytoskeletal Maintenance but Not Development ␥-Actin is required for cytoskeletal maintenance but not development Inna A. Belyantsevaa,1, Benjamin J. Perrinb,1, Kevin J. Sonnemannb,1, Mei Zhuc, Ruben Stepanyand, JoAnn McGeee, Gregory I. Frolenkovd,f, Edward J. Walshe, Karen H. Fridericic, Thomas B. Friedmana, and James M. Ervastib,2 aLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders/National Institutes of Health, Rockville, MD 20850; bDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455; cMicrobiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824; dDepartment of Physiology, University of Kentucky, Lexington, KY 40536; fMolecular Biology and Genetics Section, National Institute on Deafness and Other Communication Disorders/National Institutes of Health, Rockville, MD 20850; and eDevelopmental Auditory Physiology Laboratory, Boys Town National Research Hospital, Omaha, NE 68131 Edited by Carl Frieden, Washington University School of Medicine, St. Louis, MO, and approved April 24, 2009 (received for review January 8, 2009) ␤cyto-Actin and ␥cyto-actin are ubiquitous proteins thought to be talline array of unidirectionally oriented actin filaments (Fig. 2C) essential building blocks of the cytoskeleton in all non-muscle cells. (13–15). Despite this widely held supposition, we show that ␥cyto-actin null In the mammalian organ of Corti, the precise architecture of mice (Actg1؊/؊) are viable. However, they suffer increased mor- stereocilia is preserved for the life of the organism. Meanwhile, the tality and show progressive hearing loss during adulthood despite stereocilia actin core is reported to undergo renewal by continuous ␤ compensatory up-regulation of cyto-actin. The surprising viability actin polymerization at filament barbed ends and depolymerization ␤ ؊/؊ and normal hearing of young Actg1 mice means that cyto-actin at pointed ends, which is precisely coupled to maintain stereocilia can likely build all essential non-muscle actin-based cytoskeletal length (15, 16). The speed of stereocilia treadmilling is reported to structures including mechanosensory stereocilia of hair cells that be the same for all stereocilia of the same row and is proportional ␥ are necessary for hearing. Although cyto-actin–deficient stereo- to stereocilia length (17). Immuno-electron microscopy shows that cilia form normally, we found that they cannot maintain the in wild-type hair cells ␤cyto-actin is largely restricted to stereocilia, integrity of the stereocilia actin core. In the wild-type, ␥cyto-actin their rootlets, and the cuticular plate (2, 3, 18), whereas ␥cyto-actin localizes along the length of stereocilia but re-distributes to sites is reported to have more broad localization, including hair cell of F-actin core disruptions resulting from animal exposure to stereocilia and their rootlets, the cuticular plate in which stereocilia ؊/؊ damaging noise. In Actg1 stereocilia similar disruptions are are anchored, adherens junctions, and outer hair cell lateral walls ␥ observed even without noise exposure. We conclude that cyto- (2, 3, 18). Hair cells and their stereocilia are thus an attractive model actin is required for reinforcement and long-term stability of to study the structural consequences of perturbing actin isoform F-actin–based structures but is not an essential building block of composition. the developing cytoskeleton. ␤cyto- and ␥cyto-Actin are among the most abundant proteins in every mammalian cell, leading to the common assumption that ͉ ͉ actin cytoskeleton hearing both cytoplasmic actins are essential for function and viability. To test this supposition and to uncover the unique function of here are six genes encoding six vertebrate actins that are ␥cyto-actin, we generated a whole-body ␥cyto-actin knockout Tclassified according to where they are predominately ex- mouse (Actg1Ϫ/Ϫ). We show here that mice completely lacking ␣ ␣ ␣ ␥ Ϫ/Ϫ pressed. skeletal-Actin, smooth-actin, cardiac-actin, and smooth- ␥cyto-actin can survive to adulthood. Interestingly, Actg1 mice actin are primarily found in muscle cells, whereas cytoplasmic initially have normal hearing but develop progressive hearing ␤ ␥ cyto-actin and cyto-actin are ubiquitously and highly expressed loss during adulthood that is characterized by stereocilia actin in non-muscle cells, as reviewed elsewhere (1). Athough ␤cyto- core disruptions and stereocilia degradation. These findings led CELL BIOLOGY actin and ␥cyto-actin differ at only four biochemically similar us to conclude that ␥cyto-actin is not necessary for the formation amino acid residues in their N-termini, several lines of evidence of actin-based structures required for organogenesis and devel- suggest that each protein is functionally distinct. The amino acid ␤ ␥ opment, but is essential for maintenance of the hair cell actin sequences of cyto- and cyto-actin are each exactly conserved cytoskeleton. among avian and mammalian species. In addition, ␤cyto- and ␥ cyto-actin proteins are differentially localized (2–5) and post- Results translationally modified (6). Finally, although dominant mis- ␥ ␤ cyto-Actin Null Mice Are Viable. To determine whether there is a sense mutations in ACTB encoding cyto-actin are associated unique function of ␥ -actin that cannot be compensated by the with syndromic phenotypes including severe developmental mal- cyto other actin family members, we generated a ␥cyto-actin null formations and bilateral deafness (7), humans carrying a variety Ϫ Ϫ (Actg1 / ) mouse. Mice entirely devoid of ␥ -actin were of dominant missense mutations in ACTG1 develop postlingual cyto viable, but born at one-third of the expected Mendelian ratio, nonsyndromic progressive hearing loss (DFNA20, OMIM indicating that the absence of ␥ -actin caused some embryonic 604717) (8–11). cyto or perinatal lethality. Although the overall development of ␥cyto-Actin is widely expressed in the inner ear sensory epi- thelial cells on which mammalian hearing depends. These cells are organized in rows along the cochlea length: one row of inner Author contributions: I.A.B., B.J.P., K.J.S., R.S., J.M., G.I.F., E.J.W., K.H.F., T.B.F., and J.M.E. hair cells (IHCs) and three rows of outer hair cells (OHCs) (Fig. designed research; I.A.B., B.J.P., K.J.S., M.Z., R.S., J.M., and G.I.F. performed research; I.A.B., 2A). IHCs function as auditory receptors, converting sound B.J.P., K.J.S., M.Z., R.S., J.M., G.I.F., E.J.W., K.H.F., T.B.F., and J.M.E. analyzed data; and I.A.B., energy into neuronal signals, whereas OHCs enhance sensitivity B.J.P., K.J.S., G.I.F., K.H.F., T.B.F., and J.M.E. wrote the paper. to sound stimuli, as reviewed elsewhere (12). The apical surface The authors declare no conflict of interest. of a hair cell is topped with actin-rich microvilli-derived protru- This article is a PNAS Direct Submission. sions termed stereocilia, which deflect in response to sound 1I.A.B., B.J.P., and K.J.S. contributed equally to this work. stimuli, initiating mechanoelectrical transduction (Fig. 2B). 2To whom correspondence should be addressed. E-mail: [email protected]. ␤ ␥ cyto- and cyto-Actin are both thought to be essential compo- This article contains supporting information online at www.pnas.org/cgi/content/full/ nents of the stereocilia core (2–4), which consists of a paracrys- 0900221106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0900221106 PNAS ͉ June 16, 2009 ͉ vol. 106 ͉ no. 24 ͉ 9703–9708 Downloaded by guest on September 25, 2021 40 ␥cyto-Actin Null Mice Show Progressive Loss of Hearing. We assessed A Ϫ/Ϫ 35 hearing in wild-type and Actg1 mice by measuring auditory 30 brainstem response (ABR) thresholds. ABR objectively mea- 25 sures synchronous electrical activity generated by the neurons in 20 the ascending auditory system and can be recorded from scalp 15 Actg1+/+ electrodes by averaging responses to short tone bursts (19, 20). Mass (grams) +/- Ϫ/Ϫ 10 Actg1 We found that Actg1 mice up to 6 weeks of age had Actg1-/- near-normal ABR thresholds (Fig. 1D). However, 16-week-old 0 Actg1Ϫ/Ϫ 0 50 100 150 200 250 300 mice demonstrated a marked hearing impairment at Age (days) each frequency tested, and by 24 weeks of age were profoundly deaf (Fig. 1D). This progressive hearing loss was not found in 100 ϩ/Ϫ B Actg1+/- Actg1 littermates, which exhibited wild-type ABR thresholds 80 up to 24 weeks of age (Fig. S2) despite expressing only 50% of wild-type levels of ␥cyto-actin (Fig. 1C). 60 40 Differential Localization of ␤cyto- and ␥cyto-Actin in Developing and -/- Survival (%) Actg1 Adult Mouse Hair Cells Revealed Delayed Appearance of ␥cyto-Actin in 20 Stereocilia. Consistent with previous reports in postnatal chicken 0 and mature guinea pig or rat, both ␤cyto- and ␥cyto-actin were 0 100 200 300 detected in stereocilia (Fig. 2 D and E) and the cuticular plate Age (days) of adult wild-type mouse hair cells. The three independently ␥ C 200 +/+ generated cyto-actin-specific antibodies used did not stain any γ -actin Actg1 Ϫ/Ϫ cyto Actg1+/- structures in Actg1 hair cells (Fig. 2F), demonstrating the 150 -/- β Actg1 ␥ cyto-actin specificity of these antisera for cyto-actin. We found that during 100 embryonic development of wild-type mice, ␤cyto-actin appeared total actin 50 in the body of hair cells and subsequently in stereocilia earlier Protein level α-tubulin (% of wild-type) ␥ 0 than cyto-actin, which accumulated first in supporting cells and +/+ +/- -/- only later appeared in hair cells (Fig. 2 G–P). We observed -actin -actin ␤cyto-actin in auditory hair cell stereocilia as soon as they appear Actg1 Actg1 Actg1 γ cyto β cyto total actin around E16.5 (Fig. 2 G–I) in the basal turn of the cochlea. The ␥ D 120 first appearance of cyto-actin within stereocilia was detected 100 after stereocilia emerged at approximately E18.5 (Fig. 2 O–P).
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