Download BIOGRAPHICAL SKETCH NAME: Benjamin Perrin eRA COMMONS

OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)
BIOGRAPHICAL SKETCH
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NAME: Benjamin Perrin
eRA COMMONS USER NAME (credential, e.g., agency login): bperrin
POSITION TITLE: Assistant Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing,
include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE
(if
applicable)
Completion
Date
MM/YYYY
Iowa State University, Ames IA
B.S.
08/99
Biochemistry
Iowa State University, Ames IA
M.S.
08/99
Biochemistry
University of Wisconsin, Madison WI
PhD
12/05
Cell and Molecular
Biology
University of Wisconsin, Madison WI
Postdoctoral
06/06
Cell Biology
University of Minnesota, Minneapolis MN
Postdoctoral
8/11
Cell Biology and
Biochemistry
INSTITUTION AND LOCATION
FIELD OF STUDY
A. Personal Statement
Auditory function depends on hair cells, which convert the physical movement of sound into neuronal signals.
Humans are born with ~20,000 of these sensory cells and they are not renewed. Correspondingly, hair cell
dysfunction and degeneration causes many forms of adult onset deafness, including noise-induced and agerelated hearing loss. I am well positioned to solve fundamental questions about the cell biology of hair cells,
which will provide critical understanding necessary for progress towards developing the first therapeutic
approaches for preventing progressive hearing loss. My work thus far has focused on understanding the actinbased cytoskeleton that form stereocilia, which are the protrusions on hair cells that directly detect sound. In
early work, I developed and characterized conditional mouse knockouts and mouse mutant models to
understand how different actin isoforms and actin crosslinking proteins contribute to stereocilia maintenance
and preservation of auditory function. As an Assistant Professor, my work has focused on defining actin
dynamics in stereocilia, which has led to a new understanding of stereocilia maintenance. We are now poised
to assemble an integrated model of hair cell dysfunctions that cause age-related hearing loss.
B. Positions and Honors
Employment
01/2000 - 08/2000
9/2011 – 7/2014
8/2014 – Present
Lab Technician, Department of Biochemistry, UCLA, Los Angeles CA
Research Assistant Professor, Department Biochemistry, Molecular
Biology and Biophysics, University of Minnesota, Minneapolis MN
Assistant Professor, Department of Biology, Indiana University – Purdue University
Indianapolis, Indianapolis IN
Honors
2011
2009
8/2008 to 7/2011
8/2000 to 8/2003
Paul D. Boyer and James B. Peter Postdoctoral Award, University of Minnesota
Barnum Travel Award, University of Minnesota
NIDCD Ruth L. Kirschstein NRSA Postdoctoral Fellowship
Pre-Doctoral Fellowship, Molecular Biosciences Training Grant, University of WisconsinMadison
C. Contributions to Science
1. Distinct functions for actin isoforms – Mammals express six isoforms of actin, each encoded by a
different gene but with very similar amino acid sequences. Two of these isoforms, β-actin and γ-actin are
expressed in non-muscle cells. Their primary sequences are 99% identical, suggesting they have the same
cellular functions. However, the sequence of each isoform is identical to their avian counterpart, indicating that
a strong evolutionary pressure to maintain both isoforms. This suggests that each isoform has at least some
unique and essential functions. To address this question, I generated mouse knockout models lacking β-actin
or γ-actin proteins in sensory hair cells. While neither β-actin nor γ-actin was required for stereocilia
development or normal auditory function in young adults, each knockout mouse subsequently developed
different forms of progressive hearing loss and distinct stereocilia pathology. Therefore, β-actin and γ-actin
have overlapping developmental roles but different functions in maintaining hair cell stereocilia. This is strong
evidence that each actin isoform has some unique functions despite having nearly identical amino acid
sequences.
a) Perrin BJ, Sonnemann KJ and Ervasti JM. "β-actin and γ-actin are each dispensable for auditory hair
cell development but required for stereocilia maintenance." PLoS Genetics. 6(10):e1001158 (2010).
PMCID: PMC2954897
b) Belyantseva IA*, Perrin BJ*, Sonnemann KJ*, Zhu M, Stepanyan R, McGee J, Frolenkov GI, Walsh EJ,
Friderici KH, Friedman TB, Ervasti JM. “γ-actin is required for cytoskeletal maintenance but not
development.” PNAS. 106:9703 (2009). PMCID: PMC2701000 (*Equal contribution)
c) Perrin BJ and Ervasti JM. "The actin gene family: Function follows isoform." Cytoskeleton. 67:630
(2010). PMID: 20737541
2. Actin regulation and stereocilia maintenance - In β-actin knockout hair cells, the tallest row of stereocilia
remain intact while the heights of the shorter two rows of stereocilia become irregular. I discovered a very
similar phenotype in another mouse model, which develops age-related hearing loss due to a point mutation in
the actin crosslinking protein fascin-2. Using a biochemical approach, I demonstrated that the point mutation
ablates one of the two actin-binding sites in fascin-2, preventing actin filament crosslinking. Double mutant
mice lacking β-actin and expressing mutant fascin-2 have a more severe phenotype than either single mutant,
suggesting that stereocilia length maintenance depends on a balance between crosslinking to stabilize
filaments and normal polymerization dynamics. In both β-actin knockout and fascin-2 mutant mice, hearing
loss and stereocilia shortening only develop when mice also have reduced expression levels of the tip link
component cadherin-23, which likely results in inefficient tip link repair. This suggests that regulation of actin
dynamics is critical when tip links are dysfunctional.
a) Perrin BJ, Strandjord DM, Narayanan P, Henderson DM, Johnson KR, Ervasti JM. "β-Actin and fascin-2
cooperate to maintain stereocilia length." Journal of Neuroscience. 33:8114 (2013). PMID 23658152.
3. A new model of actin dynamics - An accurate model of stereocilia actin dynamics is essential for
understanding how stereocilia lengths are controlled. One of my key innovations was to monitor changes in βand y-actin localization within stereocilia following conditional ablation of each isoform in adult mice. Using this
approach, we found that actin is dynamic at stereocilia tips, but highly stable along the remaining length of the
stereocilia core. In collaboration with others, this work redefined actin dynamics in stereocilia from a model
that featured rapid renewal of stereocilia actin. More recently, we developed transgenic mice that inducibly
express actin-GFP, which allowed for a more detailed study of actin dynamics in stereocilia. This study
determined that actin filaments at stereocilia tips have a half-life of a few hours while actin in the stereocilia
shaft is stable for at least several months. Together, these data support a new model of stereocilia actin
dynamics. This model provides a foundation for understanding stereocilia homeostasis and the pathobiology
of the numerous deafness-causing mutations in stereocilia proteins.
a) Zhang DS, Piazza V, Perrin BJ, Rzadzinska AK, Collin Poczatek J, Prosser HM, Ervasti JM, Corey DP,
Lechene CP. "Multi-isotope imaging mass spectrometry (MIMS) reveals slow protein turnover in
stereocilia of inner ear hair cells." Nature 481:520 (2012). PMID: 22246323.
b) Narayanan P, Chatterton P, Ikeda A, Ikeda S, Corey DP, Ervasti JM, and Perrin BJ. “Length regulation
of mechanosensitive stereocilia depends on very slow actin dynamics and filament severing proteins.”
Nature Communications 6:6855 doi: 10.1038/ncomms7855 (2015). PMID: 25897778
URL for My NCBI Bibliography (13 peer-reviewed articles)
http://www.ncbi.nlm.nih.gov/sites/myncbi/benjamin.perrin.1/bibliography/45179980/public/?sort=date&direction
=ascending
D. Research Support
Ongoing Research Support
Cytoskeletal Dynamics in Stereocilia Maintenance
NIH/NIDCD 1R03DC012354-01, Perrin (PI), 4/1/2012 to 4/1/2016.
The goals of this study are to 1) measure actin dynamics in inner ear hair cell stereocilia in vivo and 2)
determine if fascin-2 crosslinking of actin filaments regulates actin isoform function in stereocilia.