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Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis

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Abstract

At embryonic day 8.5, the LIM-homeodomain factor Lmx1a is expressed throughout the otic placode but becomes developmentally restricted to non-sensory epithelia of the ear (endolymphatic duct, ductus reuniens, cochlea lateral wall). We confirm here that the ears of newborn dreher (Lmx1a dr) mutants are dysmorphic. Hair cell markers such as Atoh1 and Myo7 reveal, for the first time, that newborn Lmx1a mutants have only three sensory epithelia: two enlarged canal cristae and one fused epithelium comprising an amalgamation of the cochlea, saccule, and utricle (a “cochlear-gravistatic” endorgan). The enlarged anterior canal crista develops by fusion of horizontal and anterior crista, whereas the posterior crista fuses with an enlarged papilla neglecta that may extend into the cochlear lateral wall. In the fused endorgan, the cochlear region is distinguished from the vestibular region by markers such as Gata3, the presence of a tectorial membrane, and cochlea-specific innervation. The cochlea-like apex displays minor disorganization of the hair and supporting cells. This contrasts with the basal half of the cochlear region, which shows a vestibular epithelium-like organization of hair cells and supporting cells. The dismorphic features of the cochlea are also reflected in altered gene expression patterns. Fgf8 expression expands from inner hair cells in the apex to most hair cells in the base. Two supporting cell marker proteins, Sox2 and Prox1, also differ in their cellular distribution between the base and the apex. Sox2 expression expands in mutant canal cristae prior to their enlargement and fusion and displays a more diffuse and widespread expression in the base of the cochlear region, whereas Prox1 is not detected in the base. These changes in Sox2 and Prox1 expression suggest that Lmx1a expression restricts and sharpens Sox2 expression, thereby defining non-sensory and sensory epithelium. The adult Lmx1a mutant organ of Corti shows a loss of cochlear hair cells, suggesting that the long-term maintenance of hair cells is also disrupted in these mutants.

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Acknowledgement

We are grateful to Jennifer Kersigo, Anne Lindgren, Yuriko Mishima, and Amanda Branch for technical assistance and collection of mouse embryos, to Dr. Garret Soukup, Marsha Pierce, and Jason Pecka for help in designing and preparing primers, to Drs. Engel, Ornitz, Hogan and Chea for providing plasmids with probes, and to Dr. Huda Zoghbi for mice.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Creighton University, Omaha, NE, USA

    David H. Nichols, Sarah Pauley & Kirk W. Beisel

  2. Departments of Human Genetics and Neurology, University of Chicago, Chicago, IL, USA

    Kathleen J. Millen

  3. Department of Biology, University of Iowa, 143 Biology Building, Iowa, IA 52242, USA

    Israt Jahan & Bernd Fritzsch

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  1. David H. Nichols
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  2. Sarah Pauley
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  4. Kirk W. Beisel
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  6. Bernd Fritzsch
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Correspondence to Bernd Fritzsch.

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This work was supported by grants from the NCRR/COBRE (P20 RR 018788; D.H.N.) and NIH (RO1 DC 005590; B.F.). Parts of this investigation were conducted in a facility constructed with support of a Research Facilities Improvement Program Grant from the National Center for Research Resources, National Institutes of Health. We acknowledge the use of the confocal microscope facility of the NCCB, supported by EPSCoR EPS-0346476 (CFD 47.076), and of the University of Nebraska microarray facility, supported by NCRR/COBRE.

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Nichols, D.H., Pauley, S., Jahan, I. et al. Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis. Cell Tissue Res 334, 339–358 (2008). https://doi.org/10.1007/s00441-008-0709-2

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