The LIM homeodomain transcription factor Lmx1a shows a dynamic expression in the developing mouse ear that stabilizes in the non-sensory epithelium. Previous work showed that Lmx1a functional null mutants have an additional sensory hair cell patch in the posterior wall of a cochlear duct and have a mix of vestibular and cochlear hair cells in the basal cochlear sensory epithelium. In E13.5 mutants, Sox2-expressing posterior canal crista is continuous with an ectopic “crista sensory epithelium” located in the outer spiral sulcus of the basal cochlear duct. The medial margin of cochlear crista is in contact with the adjacent Sox2-expressing basal cochlear sensory epithelium. By E17.5, this contact has been interrupted by the formation of an intervening non-sensory epithelium, and Atoh1 is expressed in the hair cells of both the cochlear crista and the basal cochlear sensory epithelium. Where cochlear crista was formerly associated with the basal cochlear sensory epithelium, the basal cochlear sensory epithelium lacks an outer hair cell band, and gaps are present in its associated Bmp4 expression. Further apically, where cochlear crista was never present, the cochlear sensory epithelium forms a poorly ordered but complete organ of Corti. We propose that the core prosensory posterior crista is enlarged in the mutant when the absence of Lmx1a expression allows JAG1-NOTCH signaling to propagate into the adjacent epithelium and down the posterior wall of the cochlear duct. We suggest that the cochlear crista propagates in the mutant outer spiral sulcus because it expresses Lmo4 in the absence of Lmx1a.
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Agulnick AD, Taira M, Breen JJ, Tanaka, T, Dawid IB, Westphal H, (1996) Interactions of the LIM-domain-binding factor Ldbl with LIM homeodomain proteins. Nature 384 (6606):270–272
Bergstrom DE, Gagnon LH, Eicher EM (1999) Genetic and physical mapping of the dreher locus on mouse chromosome 1. Genomics 59:291–299
Bermingham NA, Hassan BA, Wang VY, Fernandez M, Banfi S, Bellen HJ, Fritzsch B, Zoghbi HY (2001) Proprioceptor pathway development is dependent on Math1. Neuron 30:411–422
Brichta AM, Goldberg JM (1998) The papilla neglecta of turtles: a detector of head rotations with unique sensory coding properties. J Neurosci 18:4314–4324
Burzynski GM, Reed X, Maragh S, Matsui T, McCallion AS (2013) Integration of genomic and functional approaches reveals enhancers at LMX1A and LMX1B. Mol Gen Genomics 288:579–589
Chang W, Lin Z, Kulessa H, Hebert J, Hogan BL, Wu DK (2008) Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements. PLoS Genet 4:e1000050
Chizhikov V, Steshina E, Roberts R, Ilkin Y, Washburn L, Millen KJ (2006a) Molecular definition of an allelic series of mutations disrupting the mouse Lmx1a (dreher) gene. Mamm Genome 17:1025
Chizhikov VV, Lindgren AG, Currle DS, Rose MF, Monuki ES, Millen KJ (2006b) The roof plate regulates cerebellar cell-type specification and proliferation. Development 133:2793–2804
Daudet N, Lewis J (2005) Two contrasting roles for Notch activity in chick inner ear development: specification of prosensory patches and lateral inhibition of hair-cell differentiation. Development 132:541–551
Daudet N, Ariza-McNaughton L, Lewis J (2007) Notch signalling is needed to maintain, but not to initiate, the formation of prosensory patches in the chick inner ear. Development 134:2369–2378
Deng M, Pan L, Xie X, Gan L (2010) Requirement for Lmo4 in the vestibular morphogenesis of mouse inner ear. Dev Biol 338:38–49
Deng Q, Andersson E, Hedlund E, Alekseenko Z, Coppola E, Panman L, Millonig JH, Brunet J-F, Ericson J, Perlmann T (2011) Specific and integrated roles of Lmx1a, Lmx1b and Phox2a in ventral midbrain development. Development 138:3399–3408
Deng M, Luo X-j, Pan L, Yang H, Xie X, Liang G, Huang L, Hu F, Kiernan AE, Gan L (2014) LMO4 functions as a negative regulator of sensory organ formation in the mammalian cochlea. J Neurosci 34:10072–10077
Deol M (1964) The origin of the abnormalities of the inner ear in dreher mice. Development 12:727–733
Dvorakova M, Jahan I, Macova I, Chumak T, Bohuslavova R, Syka J, Fritzsch B, Pavlinkova G (2016) Incomplete and delayed Sox2 deletion defines residual ear neurosensory development and maintenance. Sci Rep 6:38253
Dvorakova M, Macova I, Bohuslavova R, Anderova M, Fritzsch B, Pavlinkova G (2020) Early ear neuronal development, but not olfactory or lens development, can proceed without SOX2. Dev Biol 457:43–56
Echelard Y, Vassileva G, McMahon AP (1994) Cis-acting regulatory sequences governing Wnt-1 expression in the developing mouse CNS. Development 120:2213–2224
Elliott KL, Fritzsch B, Duncan JS (2018) Evolutionary and developmental biology provide insights into the regeneration of organ of Corti hair cells. Front Cell Neurosci 12:252
Failli V, Bachy I, Rétaux S (2002) Expression of the LIM-homeodomain gene Lmx1a (dreher) during development of the mouse nervous system. Mech Dev 118:225–228
Fritzsch B, Elliott KL (2017) Gene, cell, and organ multiplication drives inner ear evolution. Dev Biol 431:3–15
Fritzsch B, Wake M (1988) The inner ear of gymnophione amphibians and its nerve supply: a comparative study of regressive events in a complex sensory system (Amphibia, Gymnophiona). Zoomorphology 108:201–217
Fritzsch B, Nichols D, Echelard Y, McMahon A (1995) Development of midbrain and anterior hindbrain ocular motoneurons in normal and Wnt-1 knockout mice. Develop Neurobiol 27:457–469
Fritzsch B, Beisel K, Jones K, Farinas I, Maklad A, Lee J, Reichardt L (2002) Development and evolution of inner ear sensory epithelia and their innervation. J Neurobiol 53:143–156
Fritzsch B, Matei V, Nichols D, Bermingham N, Jones K, Beisel K, Wang V (2005) Atoh1 null mice show directed afferent fiber growth to undifferentiated ear sensory epithelia followed by incomplete fiber retention. Dev Dyn 233:570–583
Fritzsch B, Pan N, Jahan I, Duncan JS, Kopecky BJ, Elliott KL, Kersigo J, Yang T (2013) Evolution and development of the tetrapod auditory system: an organ of Corti-centric perspective. Evol Dev 15:63–79
Giraldez F (1998) Regionalized organizing activity of the neural tube revealed by the regulation of lmx1 in the otic vesicle. Dev Biol 203:189–200
Glover JC, Elliott KL, Erives A, Chizhikov VV, Fritzsch B (2018) Wilhelm His’ lasting insights into hindbrain and cranial ganglia development and evolution. Dev Biol 444:S14–S24
Hartman BH, Reh TA, Bermingham-McDonogh O (2010) Notch signaling specifies prosensory domains via lateral induction in the developing mammalian inner ear. Proc Natl Acad Sci 107:15792–15797
Huang M, Sage C, Li H, Xiang M, Heller S, Chen ZY (2008) Diverse expression patterns of LIM-homeodomain transcription factors (LIM-HDs) in mammalian inner ear development. Dev Dyn 237:3305–3312
Huang Y, Hill J, Yatteau A, Wong L, Jiang T, Petrovic J, Gan L, Dong L, Wu DK (2018) Reciprocal negative regulation between Lmx1a and Lmo4 is required for inner ear formation. J Neurosci 38:5429–5440
Hunter CS, Rhodes SJ (2005) LIM-homeodomain genes in mammalian development and human disease. Mol Biol Rep 32:67–77
Jones CM, Lyons KM, Hogan BL (1991) Involvement of bone morphogenetic Protein-4 (BMP-4) and Vgr-1 in morphogenesis and neurogenesis in the mouse. Development 111:531–542
Koo SK, Hill JK, Hwang CH, Lin ZS, Millen KJ, Wu DK (2009) Lmx1a maintains proper neurogenic, sensory, and non-sensory domains in the mammalian inner ear. Dev Biol 333:14–25
Kopecky BJ, Duncan JS, Elliott KL, Fritzsch B (2012) Three-dimensional reconstructions from optical sections of thick mouse inner ears using confocal microscopy. J Microsc 248:292–298
Krause C, Guzman A, Knaus P (2011) Noggin. Int J Biochem Cell Biol 43:478–481
Kuwamura M, Muraguchi T, Matsui T, Ueno M, Takenaka S, Yamate J, Kotani T, Kuramoto T, Guenet JL, Kitada K, Serikawa T (2005) Mutation at the Lmx1a locus provokes aberrant brain development in the rat. Brain Res Dev Brain Res 155:99–106
Macova I, Pysanenko K, Chumak T, Dvorakova M, Bohuslavova R, Syka J, Fritzsch B, Pavlinkova G (2019) Neurod1 is essential for the primary tonotopic organization and related auditory information processing in the midbrain. J Neurosci 39:984–1004
Mann ZF, Galvez H, Pedreno D, Chen Z, Chrysostomou E, Żak M, Kang M, Canden E, Daudet N (2017) Shaping of inner ear sensory organs through antagonistic interactions between Notch signalling and Lmx1a. Elife 6:e33323
Manzanares M, Trainor PA, Ariza-McNaughton L, Nonchev S, Krumlauf R (2000) Dorsal patterning defects in the hindbrain, roof plate and skeleton in the dreher (dr(J)) mouse mutant. Mech Dev 94:147–156
Matthews JM, Bhati M, Craig VJ, Deane JE, Jeffries C, Lee C, Nancarrow AL, Ryan DP, Sunde M (2008) Competition between LIM-binding domains. Biochem Soc Trans 36:1393–1397
Milán M, Cohen SM (2000) Temporal regulation of apterous activity during development of the Drosophila wing. Development 127:3069–3078
Millonig JH, Millen KJ, Hatten ME (2000) The mouse dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS. Nature 403:764–769
Mishima Y, Lindgren AG, Chizhikov VV, Johnson RL, Millen KJ (2009) Overlapping function of Lmx1a and Lmx1b in anterior hindbrain roof plate formation and cerebellar growth. J Neurosci 29:11377–11384
Morsli H, Tuorto F, Choo D, Postiglione MP, Simeone A, Wu DK (1999) Otx1 and Otx2 activities are required for the normal development of the mouse inner ear. Development 126:2335–2343
Neves J, Parada C, Chamizo M, Giráldez F (2011) Jagged 1 regulates the restriction of Sox2 expression in the developing chicken inner ear: a mechanism for sensory organ specification. Development 138:735–744
Nichols D, Echelard Y, McMahon A, Fritzsch B (1994) Combining biotinylated dextran amine neuronal labeling and lac-Z/β-galactosidase reporter gene labeling to study the relationship between identified neuronal populations and gene expression in the embryonic mouse nervous system. Neurosci Protocol 30:1–11
Nichols DH, Pauley S, Jahan I, Beisel KW, Millen KJ, Fritzsch B (2008) Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis. Cell Tissue Res 334:339–358
Ohyama T, Basch ML, Mishina Y, Lyons KM, Segil N, Groves AK (2010) BMP signaling is necessary for patterning the sensory and nonsensory regions of the developing mammalian cochlea. J Neurosci 30:15044–15051
Pan N, Jahan I, Kersigo J, Kopecky B, Santi P, Johnson S, Schmitz H, Fritzsch B (2011) Conditional deletion of Atoh1 using Pax2-Cre results in viable mice without differentiated cochlear hair cells that have lost most of the organ of Corti. Hear Res 275:66–80
Pan N, Jahan I, Kersigo J, Duncan JS, Kopecky B, Fritzsch B (2012) A novel Atoh1 “self-terminating” mouse model reveals the necessity of proper Atoh1 level and duration for hair cell differentiation and viability. PLoS One 7:e30358
Pauley S, Wright TJ, Pirvola U, Ornitz D, Beisel K, Fritzsch B (2003) Expression and function of FGF10 in mammalian inner ear development. Dev Dyn 227:203–215
Schrauwen I, Chakchouk I, Liaqat K, Jan A, Nasir A, Hussain S, Nickerson DA, Bamshad MJ, Ullah A, Ahmad W (2018) A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment. Hum Genet 137:471–478
Steffes G, Lorente-Cánovas B, Pearson S, Brooker RH, Spiden S, Kiernan AE, Guénet J-L, Steel KP (2012) Mutanlallemand (mtl) and belly spot and deafness (bsd) are two new mutations of Lmx1a causing severe cochlear and vestibular defects. PLoS One 7:e51065
Wadman IA, Osada H, Grutz GG, Agulnick AD, Westphal H, Forster A, Rabbitts TH (1997) The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. EMBO J 16:3145–3157
Wesdorp M, de Koning Gans PAM, Schraders M, Oostrik J, Huynen MA, Venselaar H, Beynon AJ, van Gaalen J, Piai V, Voermans N, van Rossum MM, Hartel BP, Lelieveld SH, Wiel L, Verbist B, Rotteveel LJ, van Dooren MF, Lichtner P, Kunst HPM, Feenstra I, Admiraal RJC, Yntema HG, Hoefsloot LH, Pennings RJE, Kremer H (2018) Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction. Hum Genet 137:389–400
Weston MD, Pierce ML, Jensen-Smith HC, Fritzsch B, Rocha-Sanchez S, Beisel KW, Soukup GA (2011) MicroRNA-183 family expression in hair cell development and requirement of microRNAs for hair cell maintenance and survival. Dev Dyn 240:808–819
Wu DK, Oh S-H (1996) Sensory organ generation in the chick inner ear. J Neurosci 16:6454–6462
Yamashita T, Zheng F, Finkelstein D, Kellard Z, Robert C, Rosencrance CD, Sugino K, Easton J, Gawad C, Zuo J (2018) High-resolution transcriptional dissection of in vivo Atoh1-mediated hair cell conversion in mature cochleae identifies Isl1 as a co-reprogramming factor. PLoS Genet 14:e1007552
We thank Dr. Garret Soukup, Jason Pecka, and Marsha Pierce for help designing and preparing probes and primers, Dr. Doris Wu for the Bmp4 probe plasmid, and Dr. Huda Zoghbi for mice. We also thank Dr. Kathleen Millen for a helpful discussion regarding her Lmx1a-cre line.
The study was supported by the grants of NCRR/NIGMS/COBRE (NCRR P20 RR 018788; NIGMS P20GM103471; DHN), NIH (RO1 DC 005590; R01 AG060504 BF), and National Center for Research Resources (G20RR024001). This work was carried out under research programs of Creighton University (D H. Nichols, J E. Bouma, K W. Beisel, D Z. Z. He, H Liu) and University of Iowa (B J. Kopecky, I Jahan, B Fritzsch).
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The authors declare that they have no conflict(s) of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies involving human participants performed by any of the authors.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All were mice were maintained in an AALAC certified facility under a Creighton University IACUC-approved protocol.
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Nichols, D.H., Bouma, J.E., Kopecky, B.J. et al. Interaction with ectopic cochlear crista sensory epithelium disrupts basal cochlear sensory epithelium development in Lmx1a mutant mice. Cell Tissue Res (2020). https://doi.org/10.1007/s00441-019-03163-y