Reciprocal negative regulation between Lmx1a and Lmo4 is required for inner ear formation.

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Reciprocal negative regulation between Lmx1a and Lmo4 is required for inner ear formation.

J Neurosci. 2018 May 16;:

Authors: Huang Y, Hill J, Yatteau A, Wong L, Jiang T, Petrovic J, Gan L, Dong L, Wu DK

Abstract
LIM-domain containing transcription factors (LIM-TFs) are conserved factors important for embryogenesis. The specificity of these factors in transcriptional regulation is conferred by the complexes they form with other proteins such as LIM-domain-binding (Ldb) proteins and LIM-domain only (LMO) proteins. Unlike LIM-TF, these proteins do not bind DNA directly. LMO are negative regulators of LIM-TF and they function by competing with LIM-TFs for binding to Ldbs. Although the LIM-TF Lmx1a is expressed in the developing mouse hindbrain, which provides many of the extrinsic signals for inner ear formation, conditional knockout embryos of both sexes show that the inner ear source of Lmx1a is the major contributor of ear patterning. Additionally, we have identified that the reciprocal interaction between Lmx1a and Lmo4 (a LMO protein within the inner ear) mediates formation of both vestibular and auditory structures. Lmo4 negatively regulates Lmx1a to form the three sensory cristae, the anterior semicircular canal and the shape of the utricle in the vestibule. Furthermore, this negative regulation blocks ectopic sensory formation in the cochlea. By contrast, Lmx1a negatively regulates Lmo4 in mediating epithelial resorption of the canal pouch, which gives rise to the anterior and posterior semicircular canals. We also found that Lmx1a is independently required for the formation of the endolymphatic duct and hair cells in the basal cochlear region.Significant StatementThe mammalian inner ear is a structurally complex organ responsible for detecting sound and maintaining balance. Failure to form the intricate three-dimensional structure of this organ properly during development most likely will result in sensory deficits on some level. Here we provide genetic evidence that a transcription factor, Lmx1a, interacts with its negative regulator, Lmo4, to pattern various vestibular and auditory components of the mammalian inner ear. Identifying these key molecules that mediate formation of this important sensory organ will be helpful for designing strategies and therapeutics to alleviate hearing loss and balance disorders.

PMID: 29769265 [PubMed - as supplied by publisher]

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