An Lmx1a/b allelic series reveals the role of Lmx1 genes in cochlear nuclei development
摘要
Lmx1a/b paralogous genes, which arose from the invertebrate Lmx1b-like gene, are critical for hearing in multiple vertebrate species, and mutations in these genes cause hearing deficits in humans. While the unique and redundant functions of Lmx1a/b in the inner ear are well established, their contribution to the development of the cochlear nuclei, which process and relay auditory information to the brain, is poorly understood. Since cochlear nuclei maturate postnatally, here we analyzed Lmx1a+/−;Lmx1b+/−, Lmx1a−/−, and Lmx1a−/−;Lmx1b+/− mice that survive past birth. Loss of Lmx1a reduced distinct populations of excitatory neurons in dorsal (DCN) and ventral (VCN) cochlear nuclei and their innervation from the inner ear. Additional loss of one Lmx1b copy made Lmx1a−/− phenotypes more severe, revealing that Lmx1b acts redundantly with Lmx1a. Unlike Lmx1a−/− mice, excitatory neurons were not affected in Lmx1a+/−;Lmx1b+/− mice. Thus, while cochlear nuclei are sensitive to Lmx1a/b gene dosage, these genes are not completely equivalent, and Lmx1a has a more profound role in cochlear nuclei development. Lmx1a−/− and especially Lmx1a−/−;Lmx1b+/− embryos had fewer Atoh1+ progenitors that produce excitatory neurons of the cochlear nuclei, and reduced Bmp6 expression in the roof plate, the signaling center that induces these progenitors via Bmp signaling. We found that Lmx1a is the primary regulator of Bmp6, whereas Lmx1b contributes only in the absence of Lmx1a. Thus, Lmx1a plays a major role in the formation of the mature structure and connectivity of both the DCV and VCN, and Lmx1b acts redundantly to Lmx1a but only partially compensates for Lmx1a loss.