Bastille Isle, Lee Lucy, Moncada-Reid Cynthia, Yu Wei-Ming, Sitko Austen, Yung Andrea, Zamani Mina, Christophersen Nele, Maroofian Reza, Galehdari Hamid, Babai Norbert, Vona Barbara, Moser Tobias, Goodrich Lisa
Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
Department of Neurobiology, Harvard Medical School, Boston, MA, USA; Department of Biology, Loyola University Chicago, Chicago, IL, USA.
Cell Rep. 2025 Jun 24;44(6):115796. doi: 10.1016/j.celrep.2025.115796. Epub 2025 Jun 6.
Neurons develop diverse synapses that vary in content, morphology, and size. Although transcriptional regulators of neurotransmitter identity are known, it remains unclear how synaptic features are patterned among neuronal subtypes. In the auditory system, glutamatergic synaptic properties vary across three spiral ganglion neuron (SGN) subtypes that collectively encode sound. Here, we demonstrate that Maf transcription factors combinatorially shape synaptic properties in SGNs. SGN subtypes express different ratios of c-Maf and Mafb, which act redundantly to impart subtype identities and individually to shape subtype-appropriate gene expression programs. On their own, c-Maf and Mafb have independent and opposing effects on synaptic features and hearing. A mutation in the MAFB leucine zipper domain causes deafness in humans, underscoring the importance of regulated Maf activity for hearing. Thus, functional diversity and coordinated action of Maf family members enable flexible and robust control of gene expression needed to generate synaptic heterogeneity across neuronal subtypes.
神经元会形成在成分、形态和大小上各不相同的多种突触。虽然已知神经递质特性的转录调节因子，但尚不清楚突触特征在神经元亚型之间是如何形成模式的。在听觉系统中，谷氨酸能突触特性在共同编码声音的三种螺旋神经节神经元（SGN）亚型中有所不同。在此，我们证明Maf转录因子以组合方式塑造SGN中的突触特性。SGN亚型表达不同比例的c-Maf和Mafb，它们共同作用赋予亚型特征，并分别塑造适合亚型的基因表达程序。单独来看，c-Maf和Mafb对突触特征和听力有独立且相反的影响。MAFB亮氨酸拉链结构域的突变会导致人类耳聋，这突出了受调控的Maf活性对听力的重要性。因此，Maf家族成员的功能多样性和协同作用能够灵活且有力地控制在不同神经元亚型中产生突触异质性所需的基因表达。
