Hox2 Genes Are Required for Tonotopic Map Precision and Sound Discrimination in the Mouse Auditory Brainstem

Abstract

Tonotopy is a hallmark of auditory pathways and provides the basis for sound discrimination. Little is known about the involvement of transcription factors in brainstem cochlear neurons orchestrating the tonotopic precision of pre-synaptic input. We found that in the absence of Hoxa2 and Hoxb2 function in Atoh1-derived glutamatergic bushy cells of the anterior ventral cochlear nucleus, broad input topography and sound transmission were largely preserved. However, fine-scale synaptic refinement and sharpening of isofrequency bands of cochlear neuron activation upon pure tone stimulation were impaired in Hox2 mutants, resulting in defective sound-frequency discrimination in behavioral tests. These results establish a role for Hox factors in tonotopic refinement of connectivity and in ensuring the precision of sound transmission in the mammalian auditory circuit.

Conditional Loss of Hoxa5 Function Early after Birth Impacts on Expression of Genes with Synaptic Function

“…Strikingly, very few candidate target genes are components or essential regulators of the Wnt/β-catenin, FGF, and TGF-β/Activin/BMP signaling pathways that have been identified as downstream pathways of several HOX proteins in embryonic development, neural differentiation and tumorigenesis ( Chen et al, 2005 ; Schiedlmeier et al, 2007 ; Bami et al, 2011 ; Makki and Capecchi, 2011 ; Donaldson et al, 2012 ; Carroll and Capecchi, 2015 ; Duan et al, 2015 ; Hrycaj et al, 2015 ; Roux et al, 2015 ; Karmakar et al, 2017 ; Zhang et al, 2017 ). Moreover, except from Pcp2 (see Supplementary Table S3 , line 17), none of the already identified direct or indirect targets of HOXA5 was significantly downregulated in our analysis (e.g., Ptn, Fslt1 ) ( Sanlioglu et al, 1998 ; Chen et al, 2005 ; Boucherat et al, 2013 ).…”

“…The HOX family of transcription factors gathers key regulators of embryo patterning, organ development, and cell differentiation during animal development, but also throughout adult life ( Mallo et al, 2010 ; Rezsohazy et al, 2015 ). In the central nervous system (CNS) Hox genes play critical roles in successive developmental steps, from neurulation to the establishment of neuronal networks ( Nolte and Krumlauf, 2007 ; Dasen and Jessell, 2009 ; Narita and Rijli, 2009 ; Di Bonito et al, 2013a ; Karmakar et al, 2017 ). During neurulation, combinatorial expression of Hox genes provides a segmental identity and antero-posterior patterning information to neural progenitors ( Nolte and Krumlauf, 2007 ).…”

“…During neurulation, combinatorial expression of Hox genes provides a segmental identity and antero-posterior patterning information to neural progenitors ( Nolte and Krumlauf, 2007 ). Some Hox genes remain expressed in the CNS after neurulation and they are implicated in normal tangential migration of pontine neurons, in axonal connection and arborization, in topographic connectivity, in synaptic refinement and in neuron survival ( Oury et al, 2006 ; Pasqualetti et al, 2007 ; Geisen et al, 2008 ; Di Bonito et al, 2013b ; Philippidou and Dasen, 2013 ; Bechara et al, 2015 ; Catela et al, 2016 ; Karmakar et al, 2017 ). Finally, recent evidences show that Hox genes from paralog groups 3–8 (PG3–8) display differential anterior limits of expression in the perinatal and adult hindbrain derivatives suggesting a continuing role in differentiation of neuronal derivatives after birth ( Hutlet et al, 2016 ; Tomas-Roca et al, 2016 ).…”

Cellular and Molecular Underpinnings of Neuronal Assembly in the Central Auditory System during Mouse Development

“…A new role of Hoxa2 in the AVCN has been recently reported. Hox2 genes are required for the proper innervation of Atoh1 -derived glutamatergic bushy cells by SG afferent neurons and sound-frequency discrimination, indicating a role for these Hox factors in tonotopic refinement of connectivity and in ensuring the precision of sound transmission in the mammalian auditory circuit (Karmakar et al, 2017). …”

DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory organ of Corti

“…We suggest that further study of the connection of annotated regulatory elements to immune-related genes, possibley NF-κB regulated genes in response to inflammation and noise damage, and the DNA methylation status of the elements, holds potential for developments in the field of regenerative medicine in the inner ear SE. Furthermore, we predict that cell type-specific methylome analysis of sensory versus non-sensory cells across the tonotopic map of the organ of Corti will reveal finite differential methylation that will enable us to explain the orchestration of topographic circuit assembly [75,76], and may reveal positional epigenetic information carried by tissue embedded precursors that guide later differentiation processes.…”