A Combinatorial Maf Transcription Factor Code Establishes Synaptic Heterogeneity Critical for Normal Hearing Function
Citation
Bastille, Isle. 2022. A Combinatorial Maf Transcription Factor Code Establishes Synaptic Heterogeneity Critical for Normal Hearing Function. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.Abstract
Spiral ganglion neuron (SGN) synaptic, functional, and molecular diversity is critical for hearingfunction. Heterogeneous inner hair cell (IHC)-SGN synapses transduce complex sound
information from the ear to the brain. Type I SGNs encode the frequency, timing, and intensity
of the sounds we hear. Each Type I SGN creates one to two synapses onto a single IHC.
Immunohistochemical analyses have found variations in the subunit composition and volume of
glutamate receptor puncta among SGN postsynaptic terminals. Synapses develop during the
first postnatal week in mice and acquire their mature heterogeneous properties by one month.
Single-cell RNA sequencing has shown that Type I SGNs can be divided into three molecularly
distinct subtypes (IA, IB and IC). However, the molecular drivers of SGN synaptic heterogeneity
remain elusive. MAF family transcription factors stand out as excellent candidates due to their
known roles in synapse development. To define the contributions of MAFB and CMAF to
synapse development and heterogeneity, we examined their expression patterns and assessed
conditional knock-out strains for changes in synaptic morphology, auditory response, and gene
expression. We used 10X single-cell RNA sequencing (scRNAseq) to independently assess
cMaf and Mafb RNA expression levels across Type 1 SGN subtypes and to detect changes to
synaptic genes in knockout strains. We have found that single-knockouts of CMAF and MAFB
have both opposing and additive synaptic and functional phenotypes, with particularly severe
deficits in double knockout animals. CMAF and MAFB are expressed in complementary patterns
across SGN molecular subtypes and transcriptional analyses confirm that CMAF and MAFB
contribute to subtype-specific and overall synaptic gene expression in SGNs. Here, we show
that these transcription factors create a combinatorial code across SGN subtypes to establish
the synaptic heterogeneity that is critical for normal hearing function.
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