Molecular Genetics of the Inner Ear

Welcome to the Grillet Lab

LAB NEWS

Congratulation to the team, Alix, Katharine, Shefin, Noor, Pei and Tony! https://www.jneurosci.org/content/41/15/3331 About the paper: “Hearing loss occurs frequently due to the dysfunction of the auditory sensory cells in the inner ear, which transform mechanical stimulations into electric signals. Trouillet et al. demonstrate that the......

POSTDOCTORAL SCHOLARS in Neurosciences- mechanobiology- electronic microscopy Stanford University School of Medicine Department of Otolaryngology The laboratory of Nicolas Grillet is recruiting two postdoctoral fellows to work on the molecular mechanisms of sound detection. The hair cells of the inner ear have a mechanotransduction organelle,......

We have received confirmation from the NIH that our application “High-resolution localization of the hair cell mechanotransduction channel components by immunogold-scanning electronic microscopy” will be financed for 2 years!...

RESEARCH

Genetics of Hearing and Vestibular Impairment


Hearing loss is a major health concern for our societies. In the United States of America, 17% of the adult population suffers from some degree of hearing loss. In addition, the elderly population frequently experiences debilitating hearing difficulties, and sometimes balancing issues.

 

Our goal is to identify the comprehensive list of genes required for hearing and head motion detection, and ultimately characterize the function of these genes at the molecular level.

 

This will improve our understanding of the inner ear physiology, but also will help the diagnosis of patients affected by hearing loss.

More about the Inner Ear

The inner ear contains the sensory cells that detect sound and head motion, the hair cells. In mammals, these cells are generated during the mid-gestation and will never be replaced during the entire life. The hair cells are in constant activity and their dysfunction is a major cause of deafness and peripheral vestibular disorders: they are both the core and the Achilles’ heel of the system.

More about the Genetics of Hearing loss

Hearing loss can result from exposure to excessive noise, chemicals and certain medications. However, susceptibility to deafness is generally dictated by genetic transmission. To this date, 136 human loci have been linked to hearing loss, but we know the corresponding affected genes for only 85 of them. These genes are very often required, directly or indirectly, for the proper hair cell function.

More about our Strategy

In order to identify these genes, we use mouse models either to precisely inactivate candidate genes (Reverse Genetics) or to generate randomly mutated animals and screen them for hearing or vestibular defects (Forward Genetics).

 

Using this later method, we identified the gene Loxhd1 as responsible for deafness in mice and humans (Grillet, AJHG, 2009), who are affected by a form of progressive hearing loss called DFNB77.

Function of Hair Cells and Other Inner Ear Cells

Differently from the sense of Vision, still little is known about Hearing and Balancing at their molecular level. This is due to the technical challenges associated with this organ: the paucity of the inner ear sensory cells, their inaccessibility and their fragility.

 

The inner ear is composed of two functional parts: the cochlea, which is the auditory organ, and the vestibule, organ responsible for head motion and balancing. In both parts, the sensory epithelia are composed of the sensory hair cells, called hair cells, always surrounded by supporting cells.

 

We want to characterize down to the molecular level the function of the cells that compose the inner ear, particularly the hair cells

More about Hair Cells

The hair cells have different functions:

1) to detect the mechanical stimuli induced by sound, and
2) to transmit this information to the central nervous system through their synapses.

More about Mechanotransduction

We are particularly interested in the organelle of mechanotransduction, the hair bundle. The hair bundle is located at the apical surface of the hair cells, consisting of a precise staircase arrangement of membrane protrusions filled with filamentous actin, bound to each other by extracellular linkages. Upon stimulation, force engages the bundle, and opening large conductance mechanically gated channels, generating the current that allows the sense of hearing and balancing. Cochlear hair bundles present different morphologies along the cochlea, differing from the elongated ones found in the vestibule.

 

We are interested in understanding the uniqueness of the hair bundles by identifying their key components and their functions.

More about our Strategy

In order to identify the key components of the stereocilia bundle we will be using different approaches such as mouse Genetics, Electronic Microscopy, Electrophysiology or Biophysics.

 

By using a mouse model, we have previously showed that the USH1C protein Harmonin is required for the proper sensitivity of the hair bundle to mechanical stimulation (Grillet et al., Neuron, 2009). More recently, we also have shown that the protein TMHS is associated with part of the mechanotransduction machinery and influences the mechano-channel properties (Xiong, Cell, 2012).

APPROACHES

molecular biology icon
Electrophysiology icon
Biochemistry icon
mouse genetics and mouse audiometry
Cellular biology icon
Bioinformatics icon
Histology icon

THE TEAM

Principal Investigator

NICOLAS GRILLET, Ph.D.
Phone: 650.497.9393
ngrillet@stanford.edu

Post-Doctoral Fellow

KATHARINE MILLER Ph.D.
Phone: 650-498-5229
kkmiller@stanford.edu

Post-Doctoral Fellow

PEI WANG Ph.D.
Phone: 571-376-0856
wangpei@stanford.edu

Fellow

Undergraduate Student

SIDDHANT SURI DHAWAN
Phone: 650-723-1831
sidsd27@stanford.edu

Undergraduate Student

ARUN MOMMILETI

Administrative Associate

STUART JEUNG

Phone: 650-721-1032

stuartj7@stanford.edu

Finance Manager

HANNA SY

Phone: 650-497-0262

hauyeung@stanford.edu

ALUMNI

Post-Doctoral trainees

ALIX TROUILLET : Post-Doctoral Fellow, Geneva

MATTIA CARRARO : Co-Founder at Science Meets Design Inc.

DILETTA POZZI : Research Scientist, SISSA, Italy

Research Associate

NAVID ZEBARJADI : Ph.D. student, UCSC

Undergraduate Students

ELLEN OUYANG

MARY ALEKSEEVA

BINH NGUYEN

High School Students

SELENA YUAN

SYDNEY CHEEK

SELECTED PUBLICATIONS

Loxhd1 mutations cause mechanotransduction defects in cochlear hair cells.

Trouillet A, Miller KK, George SS, Wang P, Ali NE, Ricci A, Grillet N.

J Neurosci. 2021, 14 April 2021, 41 (15) 3331-3343

A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58.

Lezirovitz K, Vieira-Silva GA, Batissoco AC, Levy D, Kitajima JP, Trouillet A, Ouyang E, Zebarjadi N, Sampaio-Silva J, Pedroso-Campos V, Nascimento LR, Sonoda CY, Borges VM, Vasconcelos LG, Beck RMO, Grasel SS, Jagger DJ, Grillet N, Bento RF, Mingroni-Netto RC, Oiticica J.

Hum Mol Genet. 2020 Jun 3;29(9):1520-1536.

Dual regulation of planar polarization by secreted Wnts and Vangl2 in the developing mouse cochlea.
Najarro EH, Huang J, Jacobo A, Quiruz LA, Grillet N, Cheng AG.
Development. 2020 Oct 5;147(19)

Osmotic stabilization prevents cochlear synaptopathy after blast trauma.

Kim J, Xia A, Grillet N, Applegate BE, Oghalai JS.

Proc Natl Acad Sci U S A. 2018 May 22;115(21):E4853-E4860. doi: 10.1073/pnas.1720121115. Epub 2018 May 7.

Mechanosensory hair cells express two molecularly distinct mechanotransduction channels.

Wu Z*, Grillet N*, Zhao B, Cunningham C, Harkins-Perry S, Coste B, Ranade S, Zebarjadi N, Beurg M, Fettiplace R, Patapoutian A, Müller U.

Nat. Neurosci. 2017 Jan;20(1):24-33. * Shared first-authorship   PubMed    PDF

Two-Dimensional Cochlear Micromechanics Measured In Vivo Demonstrate Radial Tuning within the Mouse Organ of Corti.

Lee HY, Raphael PD, Xia A, Kim J, Grillet N, Applegate BE, Ellerbee Bowden AK, Oghalai JS.

J Neurosci. 2016; 36(31):8160-73.  PubMed   PDF

Neuroplastin Isoform Np55 Is Expressed in the Stereocilia of Outer Hair Cells and Required for Normal Outer Hair Cell Function.

Zeng WZ*, Grillet N*, Dewey JB, Trouillet A, Krey JF, Barr-Gillespie PG, Oghalai JS, Müller U.

J Neurosci. 2016 Aug 31;36(35):9201-16. * Shared first-authorship  PubMed    PDF

TMIE Is an Essential Component of the Mechanotransduction Machinery of Cochlear Hair Cells.

Zhao B, Wu Z, Grillet N, Yan L, Xiong W, Harkins-Perry S, Müller U.

Neuron. 2014 Dec 3;84(5):954-67. PubMed PDF

Using injectoporation to deliver genes to mechanosensory hair cells.

Xiong W, Wagner TF, Linxuan Y, Grillet N, Müller U.

Nat Protoc. 2014 Oct;9(10):2438-49. PubMed  PDF

TMHS is an integral component of the mechanotransduction machinery of cochlearhair cells.

Xiong W, Grillet N, Elledge HM, Wagner TF, Zhao B, Johnson KR, Kazmierczak P, Müller U.

Cell. 2012 Dec 7;151(6):1283-95. PubMed PDF

Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans.

Grillet N, Schwander M, Hildebrand MS, Sczaniecka A, Kolatkar A, Velasco J, Webster JA, Kahrizi K, Najmabadi H, Kimberling WJ, Stephan D, Bahlo M, Wiltshire T, Tarantino LM, Kuhn P, Smith RJ, Müller U.

Am J Hum Genet. 2009 Sep;85(3):328-37. PubMed PDF

Harmonin mutations cause mechanotransduction defects in cochlear hair cells.

Grillet N, Xiong W, Reynolds A, Kazmierczak P, Sato T, Lillo C, Dumont RA, Hintermann E, Sczaniecka A, Schwander M, Williams D, Kachar B, Gillespie PG, Müller U.

Neuron. 2009 May 14;62(3):375-87. PubMed PDF

JOIN US

2 positions are open for post-doctoral training or advanced undergraduate students

 

  • Localizing proteins involved in hair cell mechanotransduction at high-resolution using electronic microscopy

 

  • Studying the function of the deafness gene LOXHD1 using in vitro model.

 

To apply contact Nicolas Grillet at ngrillet@stanford.edu


DIRECTIONS

CONTACT INFORMATION

Location &

Mailing Address:

Otolaryngology Department
Stanford School of Medicine
Stanford University
240 Pasteur Drive
BioMedical Innovation (BMI)building
Lab: Room 1400
Office: Room 1654
Stanford, CA 94305

Office: (650) 497-9393
Lab: (650) 498-5229
Fax: (650) 721-2163

Shipping Address:

Otolaryngology Department
Stanford School of Medicine
Stanford University
1291 Welch Road
BioMedical Innovation (BMI)building
Lab: Room 1400, GRILLET LAB
Office: Room 1654
Stanford, CA 94305

Email: ngrillet@stanford.edu
Phone: (650) 497-9393
Fax: (650) 721-2163

Lab showcase at the California Academy of Sciences, San Francisco

Exploring Sounds and Science

(February 20th 2020, nightlife Noise Pop Fest Showcase)

LAB LIFE

SCIENTIFIC PICTURES GALLERY

Sometimes pictures are more telling than words to describe scientific experiments.

We present here some images from our research on the inner ear.

These pictures are copyright protected; please contact the lab to obtain permission for use.

HISTOLOGY

MOLECULAR
BIOLOGY

MOUSE GENETICS

FLUORESCENCE MICROSCOPY

SCANNING EM

TRANSMISSION
E M

BIOINFORMATICS

COVERS

THANK YOU FOR YOUR SUPPORT

We want to warmly thank the donors of the Stanford Initiative to Cure Hearing Loss for their support!!! Your participation makes a real difference for our endeavor.

 

If you want to foster our research, you too can become a contributor to the Grillet lab. Simply click the “Contribute” button below. In “Special Instructions/Other Designation” specify “Grillet lab”.