Journal Club: SHANK2, synapse protein in the brain, is in sensory hair cells and regulate stereocilia arrangement

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Today's journal article

Choi HS, Park H, Min H, Kim KS, Kim SM, Li J, Liu C, Ko HW, Lee MG, Song L, Zhao B, Bok J. SHANK2 establishes auditory hair bundle architecture essential for mammalian hearing. 

Why I picked this article

This research investigates the role of a specific protein called SHANK2 in controlling the geometry of specialised structures in the sensory hair cells, and how it affects hearing, especially for high-frequency sounds.

Hair cells in the cochlea are beautifully engineered to detect sounds; our cochlea has two types of hair cells, inner hair cells and outer hair cells, to perform different roles in hearing. Both types of hair cells sense sound waves by moving tiny structures called stereocilia, which are "hair-like" structures arranged in precise geometries on one side of the cell. In each hair cell, there are ~ 100 stereocilia, but in the inner hair cells, they are arranged to form a bundle, while in outer hair cells, they are arranged to form a V-shape. This V-shaped alignment of stereocilia emerges during development and is thought to be critical for the synchronised response of hair cells to sound waves, and hence the sensitivity of our hearing. 

SHANK2 is a protein that regulates synapses in the brain. SHANK2 is a key protein investigated in relation to autism spectrum disorders. This research investigated where/if SHANK2 protein is also found in the cochlea, and what the role of SHANK2 may be in the cochlea. 

Some of the research findings

SHANK2 in the cochlear hair cells: 

  • SHANK2 was found on the apical surface of developing hair cells. The apical surface is where you find stereocilia. However, the location of SHANK2 was on the other side of the apical surface compared to the stereocilia bundle. 
  • The location of SHANK2 was examined from embryonic day 15.5 mice embryo ~ postnatal day 5. In mice, the hearing function kicks in at postnatal day 14. So SHANK2 is found in the cochlea from a very early development phase of the cochlea. 
Figure 1B. SHANK2 protein visualised by green color, compared to where stereocilia form (dotted line). Choi et al. (2025)

SHANK2 Deficiency: 

  • When the cochlear from SHANK2 knockout mice was examined, the stereocilia had an abnormal number and shape by postnatal day 7. Stereocilia were still present; however, they often had wavy and asymmetric organisation or were fragmented. 
  • Assessment at 3-week-old mice showed that SHANK2-deficient mice had less outer hair cell functionality, particularly at high frequency. 
  • Researchers created conditional knockout mice, where SHANK2 was deficient in hair cells only (Gfi1Cre, Shank2lox/lox), and in auditory neurons only (Bhlhe22Cre, Shanklox/lox), to confirm that the observed effect is due to loss of SHANK2 from hair cells. 
How SHANK2 may be connected with other signalling proteins that coordinate stereocilia formation:

  • Researchers used yeast two-hybrid screening in search of how SHANK2 may coordinate hair cell stereocilia formation in the cochlea. 
  • RAS-related protein 1B (RAP1B) came up as a potential candidate that interacts with SHANK2.
  • RAP1 is a protein known to regulate cell architecture. 
  • After yet another extensive study using genetically modified mice where RAP1 is now removed, researchers showed that the loss of RAP1 protein leads to SHANK2 losing its normal location and function in the cochlea. 

Overall, the study showed SHANK2 in the cochlea to be part of a group of proteins regulating how stereocilia are formed and aligned to enable sensitive hearing. 

Haruna's takeaway

Biology is amazing because important coordination and synchronisation happen at the organ level (Physiology), at the cell level (Cell Biology) and at the protein/molecule level (molecular biology? protein-protein interaction). The stereocilia bundle and its highly ordered arrangements on a particular surface of the outer hair cells require coordination within each single cell to achieve. Because SHANK2 in the brain regulate synapses, it's quite surprising that SHANK2 in the cochlea does something very different by coordinating not the synapse, but the stereocilia arrangement. We look forward to future studies on SHANK2 in the cochlea to understand how SHANK2 may interact with different proteins that make up the physical structures of the stereocilia. 

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This is Haruna's 36/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.