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

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Τίτλος: Differential vulnerability of cochlear nuclei to Lmx1 deficiency: abnormal patterning and implications for auditory circuitry.
Συγγραφείς: Iskusnykh I; Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA., Yamoah EN; Department of Translational Sciences, University of Arizona, College of Medicine-Phoenix, AZ 85004, USA., Chizhikov VV; Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA., Fritzsch B; Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: bfritzsch@unmc.edu.
Πηγή: Neuroscience letters [Neurosci Lett] 2026 Aug; Vol. 883, pp. 138669. Date of Electronic Publication: 2026 Jun 30.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Scientific Publishers Ireland Country of Publication: Ireland NLM ID: 7600130 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7972 (Electronic) Linking ISSN: 03043940 NLM ISO Abbreviation: Neurosci Lett Subsets: MEDLINE
Imprint Name(s): Publication: Limerick : Elsevier Scientific Publishers Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.
Ιατρικοί όροι (MeSH): Cochlear Nucleus*/metabolism , Cochlear Nucleus*/embryology , Cochlear Nucleus*/growth & development , LIM-Homeodomain Proteins*/genetics , LIM-Homeodomain Proteins*/deficiency , LIM-Homeodomain Proteins*/metabolism , Transcription Factors*/genetics , Transcription Factors*/deficiency , Transcription Factors*/metabolism , Auditory Pathways*/metabolism, Animals ; Mice, Knockout ; Mice
Περίληψη: 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.
(Copyright © 2026 Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References: Nature. 2000 Feb 17;403(6771):764-9. (PMID: 10693804)
J Neurosci. 2009 Sep 9;29(36):11123-33. (PMID: 19741118)
Neuron. 2005 Jul 21;47(2):201-13. (PMID: 16039563)
Nat Genet. 1998 May;19(1):51-5. (PMID: 9590288)
Neurosci Lett. 2023 May 29;806:137244. (PMID: 37055006)
Front Neural Circuits. 2017 Apr 19;11:18. (PMID: 28469562)
J Neurocytol. 1991 Jan;20(1):17-25. (PMID: 1709203)
Dev Biol. 2018 Dec 1;444 Suppl 1:S14-S24. (PMID: 29447907)
J Comp Neurol. 2021 Nov;529(16):3633-3654. (PMID: 34235739)
Dev Biol. 2017 Dec 1;432(1):34-42. (PMID: 27742210)
Brain Res Bull. 2003 Jun 15;60(5-6):457-74. (PMID: 12787867)
Front Cell Neurosci. 2017 Apr 24;11:114. (PMID: 28484373)
J Neurosci. 2016 Mar 02;36(9):2691-710. (PMID: 26937009)
Mamm Genome. 2006 Oct;17(10):1025-32. (PMID: 17019651)
Cell Tissue Res. 2019 Oct;378(1):15-32. (PMID: 31201541)
J Neurosci. 2014 Apr 2;34(14):4786-800. (PMID: 24695699)
J Comp Neurol. 2004 Nov 15;479(3):309-27. (PMID: 15457503)
Mol Neurobiol. 2020 Dec;57(12):5307-5323. (PMID: 32880858)
Front Neural Circuits. 2017 Apr 13;11:25. (PMID: 28450830)
Neuroscience. 2021 Jan 1;452:247-264. (PMID: 33246067)
Development. 2009 Jun;136(12):2049-58. (PMID: 19439493)
Annu Rev Neurosci. 2024 Aug;47(1):1-20. (PMID: 38360566)
Nat Commun. 2025 Jan 9;16(1):489. (PMID: 39788966)
Front Cell Dev Biol. 2022 Feb 17;10:845461. (PMID: 35252209)
Cell Tissue Res. 2026 Apr 17;404(1):. (PMID: 41991696)
PLoS Genet. 2023 Sep 22;19(9):e1010933. (PMID: 37738262)
J Comp Neurol. 1976 Nov 1;170(1):107-21. (PMID: 61976)
J Assoc Res Otolaryngol. 2026 Feb;27(1):5-24. (PMID: 41491447)
J Neurosci. 2009 Sep 9;29(36):11377-84. (PMID: 19741143)
Int J Mol Sci. 2021 Apr 18;22(8):. (PMID: 33919542)
J Neurosci. 2019 Feb 6;39(6):984-1004. (PMID: 30541910)
Grant Information: R01 DC015135 United States DC NIDCD NIH HHS; R01 DC022866 United States DC NIDCD NIH HHS; R01 DC016099 United States DC NIDCD NIH HHS; R01 DC015252 United States DC NIDCD NIH HHS; P01 AG051443 United States AG NIA NIH HHS; R01 NS127973 United States NS NINDS NIH HHS; R01 AG060504 United States AG NIA NIH HHS
Contributed Indexing: Keywords: Central auditory projections; Cochlear nuclei; Inner ear; Lmx1a; Lmx1b; Rhombic lip
Substance Nomenclature: 0 (LIM-Homeodomain Proteins)
0 (Transcription Factors)
0 (Lmx1a protein, mouse)
0 (LIM homeobox transcription factor 1 beta)
Entry Date(s): Date Created: 20260630 Date Completed: 20260806 Latest Revision: 20260910
Update Code: 20260910
PubMed Central ID: PMC13552370
DOI: 10.1016/j.neulet.2026.138669
PMID: 42379263
Βάση Δεδομένων: MEDLINE
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  Data: Differential vulnerability of cochlear nuclei to Lmx1 deficiency: abnormal patterning and implications for auditory circuitry.
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  Data: <searchLink fieldCode="AU" term="%22Iskusnykh+I%22">Iskusnykh I</searchLink>; Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.<br /><searchLink fieldCode="AU" term="%22Yamoah+EN%22">Yamoah EN</searchLink>; Department of Translational Sciences, University of Arizona, College of Medicine-Phoenix, AZ 85004, USA.<br /><searchLink fieldCode="AU" term="%22Chizhikov+VV%22">Chizhikov VV</searchLink>; Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.<br /><searchLink fieldCode="AU" term="%22Fritzsch+B%22">Fritzsch B</searchLink>; Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: bfritzsch@unmc.edu.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Elsevier+Scientific+Publishers+Ireland%22">Elsevier Scientific Publishers Ireland </searchLink><i>Country of Publication: </i>Ireland <i>NLM ID: </i>7600130 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1872-7972 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2203043940%22">03043940 </searchLink><i>NLM ISO Abbreviation: </i>Neurosci Lett <i>Subsets: </i>MEDLINE
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  Data: <searchLink fieldCode="MM" term="%22Cochlear+Nucleus%22">Cochlear Nucleus*</searchLink>/<searchLink fieldCode="MM" term="%22Cochlear+Nucleus+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Cochlear+Nucleus%22">Cochlear Nucleus*</searchLink>/<searchLink fieldCode="MM" term="%22Cochlear+Nucleus+embryology%22">embryology</searchLink> <br /><searchLink fieldCode="MM" term="%22Cochlear+Nucleus%22">Cochlear Nucleus*</searchLink>/<searchLink fieldCode="MM" term="%22Cochlear+Nucleus+growth+%26+development%22">growth & development</searchLink> <br /><searchLink fieldCode="MM" term="%22LIM-Homeodomain+Proteins%22">LIM-Homeodomain Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22LIM-Homeodomain+Proteins+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22LIM-Homeodomain+Proteins%22">LIM-Homeodomain Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22LIM-Homeodomain+Proteins+deficiency%22">deficiency</searchLink> <br /><searchLink fieldCode="MM" term="%22LIM-Homeodomain+Proteins%22">LIM-Homeodomain Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22LIM-Homeodomain+Proteins+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Transcription+Factors%22">Transcription Factors*</searchLink>/<searchLink fieldCode="MM" term="%22Transcription+Factors+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Transcription+Factors%22">Transcription Factors*</searchLink>/<searchLink fieldCode="MM" term="%22Transcription+Factors+deficiency%22">deficiency</searchLink> <br /><searchLink fieldCode="MM" term="%22Transcription+Factors%22">Transcription Factors*</searchLink>/<searchLink fieldCode="MM" term="%22Transcription+Factors+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Auditory+Pathways%22">Auditory Pathways*</searchLink>/<searchLink fieldCode="MM" term="%22Auditory+Pathways+metabolism%22">metabolism</searchLink><br /><searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%2C+Knockout%22">Mice, Knockout</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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<superscript>-/-</superscript> and Lmx1a<superscript>-/-</superscript>;Lmx1b<superscript>+/-</superscript> 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.<br /> (Copyright © 2026 Elsevier B.V. All rights reserved.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
– Name: Ref
  Label: References
  Group: RefInfo
  Data: Nature. 2000 Feb 17;403(6771):764-9. (PMID: <searchLink fieldCode="PM" term="%2210693804%22">10693804)</searchLink><br />J Neurosci. 2009 Sep 9;29(36):11123-33. (PMID: <searchLink fieldCode="PM" term="%2219741118%22">19741118)</searchLink><br />Neuron. 2005 Jul 21;47(2):201-13. (PMID: <searchLink fieldCode="PM" term="%2216039563%22">16039563)</searchLink><br />Nat Genet. 1998 May;19(1):51-5. (PMID: <searchLink fieldCode="PM" term="%229590288%22">9590288)</searchLink><br />Neurosci Lett. 2023 May 29;806:137244. (PMID: <searchLink fieldCode="PM" term="%2237055006%22">37055006)</searchLink><br />Front Neural Circuits. 2017 Apr 19;11:18. (PMID: <searchLink fieldCode="PM" term="%2228469562%22">28469562)</searchLink><br />J Neurocytol. 1991 Jan;20(1):17-25. (PMID: <searchLink fieldCode="PM" term="%221709203%22">1709203)</searchLink><br />Dev Biol. 2018 Dec 1;444 Suppl 1:S14-S24. (PMID: <searchLink fieldCode="PM" term="%2229447907%22">29447907)</searchLink><br />J Comp Neurol. 2021 Nov;529(16):3633-3654. (PMID: <searchLink fieldCode="PM" term="%2234235739%22">34235739)</searchLink><br />Dev Biol. 2017 Dec 1;432(1):34-42. (PMID: <searchLink fieldCode="PM" term="%2227742210%22">27742210)</searchLink><br />Brain Res Bull. 2003 Jun 15;60(5-6):457-74. (PMID: <searchLink fieldCode="PM" term="%2212787867%22">12787867)</searchLink><br />Front Cell Neurosci. 2017 Apr 24;11:114. (PMID: <searchLink fieldCode="PM" term="%2228484373%22">28484373)</searchLink><br />J Neurosci. 2016 Mar 02;36(9):2691-710. (PMID: <searchLink fieldCode="PM" term="%2226937009%22">26937009)</searchLink><br />Mamm Genome. 2006 Oct;17(10):1025-32. (PMID: <searchLink fieldCode="PM" term="%2217019651%22">17019651)</searchLink><br />Cell Tissue Res. 2019 Oct;378(1):15-32. (PMID: <searchLink fieldCode="PM" term="%2231201541%22">31201541)</searchLink><br />J Neurosci. 2014 Apr 2;34(14):4786-800. (PMID: <searchLink fieldCode="PM" term="%2224695699%22">24695699)</searchLink><br />J Comp Neurol. 2004 Nov 15;479(3):309-27. (PMID: <searchLink fieldCode="PM" term="%2215457503%22">15457503)</searchLink><br />Mol Neurobiol. 2020 Dec;57(12):5307-5323. (PMID: <searchLink fieldCode="PM" term="%2232880858%22">32880858)</searchLink><br />Front Neural Circuits. 2017 Apr 13;11:25. (PMID: <searchLink fieldCode="PM" term="%2228450830%22">28450830)</searchLink><br />Neuroscience. 2021 Jan 1;452:247-264. (PMID: <searchLink fieldCode="PM" term="%2233246067%22">33246067)</searchLink><br />Development. 2009 Jun;136(12):2049-58. (PMID: <searchLink fieldCode="PM" term="%2219439493%22">19439493)</searchLink><br />Annu Rev Neurosci. 2024 Aug;47(1):1-20. (PMID: <searchLink fieldCode="PM" term="%2238360566%22">38360566)</searchLink><br />Nat Commun. 2025 Jan 9;16(1):489. (PMID: <searchLink fieldCode="PM" term="%2239788966%22">39788966)</searchLink><br />Front Cell Dev Biol. 2022 Feb 17;10:845461. (PMID: <searchLink fieldCode="PM" term="%2235252209%22">35252209)</searchLink><br />Cell Tissue Res. 2026 Apr 17;404(1):. (PMID: <searchLink fieldCode="PM" term="%2241991696%22">41991696)</searchLink><br />PLoS Genet. 2023 Sep 22;19(9):e1010933. (PMID: <searchLink fieldCode="PM" term="%2237738262%22">37738262)</searchLink><br />J Comp Neurol. 1976 Nov 1;170(1):107-21. (PMID: <searchLink fieldCode="PM" term="%2261976%22">61976)</searchLink><br />J Assoc Res Otolaryngol. 2026 Feb;27(1):5-24. (PMID: <searchLink fieldCode="PM" term="%2241491447%22">41491447)</searchLink><br />J Neurosci. 2009 Sep 9;29(36):11377-84. (PMID: <searchLink fieldCode="PM" term="%2219741143%22">19741143)</searchLink><br />Int J Mol Sci. 2021 Apr 18;22(8):. (PMID: <searchLink fieldCode="PM" term="%2233919542%22">33919542)</searchLink><br />J Neurosci. 2019 Feb 6;39(6):984-1004. (PMID: <searchLink fieldCode="PM" term="%2230541910%22">30541910)</searchLink>
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  Data: R01 DC015135 United States DC NIDCD NIH HHS; R01 DC022866 United States DC NIDCD NIH HHS; R01 DC016099 United States DC NIDCD NIH HHS; R01 DC015252 United States DC NIDCD NIH HHS; P01 AG051443 United States AG NIA NIH HHS; R01 NS127973 United States NS NINDS NIH HHS; R01 AG060504 United States AG NIA NIH HHS
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  Data: <i>Keywords: </i>Central auditory projections; Cochlear nuclei; Inner ear; Lmx1a; Lmx1b; Rhombic lip
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      – TitleFull: Differential vulnerability of cochlear nuclei to Lmx1 deficiency: abnormal patterning and implications for auditory circuitry.
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