Abstract
Rhombomeres (r) contribute to brainstem auditory nuclei during development. Hox genes are determinants of rhombomere-derived fate and neuronal connectivity. Little is known about the contribution of individual rhombomeres and their associated Hox codes to auditory sensorimotor circuitry. Here, we show that r4 contributes to functionally linked sensory and motor components, including the ventral nucleus of lateral lemniscus, posterior ventral cochlear nuclei (VCN), and motor olivocochlear neurons. Assembly of the r4-derived auditory components is involved in sound perception and depends on regulatory interactions between Hoxb1 and Hoxb2. Indeed, in Hoxb1 and Hoxb2 mutant mice the transmission of low-level auditory stimuli is lost, resulting in hearing impairments. On the other hand, Hoxa2 regulates the Rig1 axon guidance receptor and controls contralateral projections from the anterior VCN to the medial nucleus of the trapezoid body, a circuit involved in sound localization. Thus, individual rhombomeres and their associated Hox codes control the assembly of distinct functionally segregated sub-circuits in the developing auditory brainstem.
Highlights
The mammalian brainstem plays a crucial role in the regulation of many vital functions through a complex system of reflex arcs and relays information to higher brain centers through interconnected neuronal circuits
Sound perception and sound localization are controlled by two distinct circuits in the central nervous system
We show that a spatially restricted region of the brainstem, the rhombomere 4, and two members of the Hox gene family, Hoxb1 and Hoxb2, are directly implicated in the development of the circuit leading to sound perception and sound amplification
Summary
The mammalian brainstem plays a crucial role in the regulation of many vital functions through a complex system of reflex arcs and relays information to higher brain centers through interconnected neuronal circuits. Individual rhombomeres give rise to distinct portions of sensory and motor columns depending on the position of progenitors along the dorso-ventral (D-V) axis, respectively [1], generating nuclei of multi-segmental origin and topographic patterns of connectivity [2,3,4,5,6,7]. Vestibular nuclei originate from different rhombomeres and display specific sets of axonal trajectories with distinct targets [3,4,8,9]. Regional patterning along the A-P axis and specific D-V determinants intersect to determine sub-circuit connectivity within functionally related longitudinal neuronal columns
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