Differential vulnerability of cochlear nuclei to Lmx1 deficiency: abnormal patterning and implications for auditory...

Precise regulation of progenitor identity is essential for the formation of functional auditory circuits. Cochlear nuclei arise from two major progenitor populations: Atoh1-expressing progenitors generate excitatory glutamatergic neurons, while Ptf1a-expressing progenitors generate inhibitory GABAergic and glycinergic neurons. Lmx1a and Lmx1b, expressed in the hindbrain roof plate, maintain Atoh1 expression in lower rhombic lip progenitors that give rise to excitatory neurons of the cochlear nuclei. Detailed analysis using dye tracing of cochlear and vestibular central projections revealed an overall reduction of input in both Lmx1a knockout mice and Lmx1a knockout mice with additonal loss of one copy of Lmx1b, although projections to the dorsal cochlear nucleus (DCN) remain relatively preserved. Dye insertion at the crossing of the acoustic stria demonstrate a progressive loss of the ventral acoustic stria (VAS) and its altered trajectory between the trigeminal and restiform body in Lmx1a^-/- and Lmx1a^-/-;Lmx1b^+/- mice. Together, these data show that the anteroventral cochlear nucleus (AVCN) is most severely affected at both embryonic and postnatal stages, showing loss and reduction of central projections. Ultimately, these findings identify Lmx1-dependent regulatory activity as a critical checkpoint for the proper development and connectivity of auditory pathways.