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Cover ArticleResearch Articles, Development/Plasticity/Repair

Gli3 Regulates Vomeronasal Neurogenesis, Olfactory Ensheathing Cell Formation, and GnRH-1 Neuronal Migration

Ed Zandro M. Taroc, Ankana S. Naik, Jennifer M. Lin, Nicolas B. Peterson, David L. Keefe Jr., Elizabet Genis, Gabriele Fuchs, Ravikumar Balasubramanian and Paolo E. Forni
Journal of Neuroscience 8 January 2020, 40 (2) 311-326; DOI: https://doi.org/10.1523/JNEUROSCI.1977-19.2019
Ed Zandro M. Taroc
1Department of Biological Sciences; The RNA Institute, and the Center for Neuroscience Research; University at Albany, State University of New York, Albany, New York 12222, and
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Ankana S. Naik
1Department of Biological Sciences; The RNA Institute, and the Center for Neuroscience Research; University at Albany, State University of New York, Albany, New York 12222, and
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Jennifer M. Lin
1Department of Biological Sciences; The RNA Institute, and the Center for Neuroscience Research; University at Albany, State University of New York, Albany, New York 12222, and
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Nicolas B. Peterson
1Department of Biological Sciences; The RNA Institute, and the Center for Neuroscience Research; University at Albany, State University of New York, Albany, New York 12222, and
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David L. Keefe Jr.
2Harvard Reproductive Sciences Center and The Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
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Elizabet Genis
1Department of Biological Sciences; The RNA Institute, and the Center for Neuroscience Research; University at Albany, State University of New York, Albany, New York 12222, and
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Gabriele Fuchs
1Department of Biological Sciences; The RNA Institute, and the Center for Neuroscience Research; University at Albany, State University of New York, Albany, New York 12222, and
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Ravikumar Balasubramanian
2Harvard Reproductive Sciences Center and The Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
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Paolo E. Forni
1Department of Biological Sciences; The RNA Institute, and the Center for Neuroscience Research; University at Albany, State University of New York, Albany, New York 12222, and
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Abstract

During mammalian development, gonadotropin-releasing-hormone-1 neurons (GnRH-1ns) migrate from the developing vomeronasal organ (VNO) into the brain asserting control of pubertal onset and fertility. Recent data suggest that correct development of the olfactory ensheathing cells (OEC) is imperative for normal GnRH-1 neuronal migration. However, the full ensemble of molecular pathways that regulate OEC development remains to be fully deciphered. Loss-of-function of the transcription factor Gli3 is known to disrupt olfactory development, however, if Gli3 plays a role in GnRH-1 neuronal development is unclear. By analyzing Gli3 extra-toe mutants (Gli3Xt/Xt), we found that Gli3 loss-of-function compromises the onset of achaete-scute family bHLH transcription factor 1 (Ascl-1)+ vomeronasal progenitors and the formation of OEC in the nasal mucosa. Surprisingly, GnRH-1 neurogenesis was intact in Gli3Xt/Xt mice but they displayed significant defects in GnRH-1 neuronal migration. In contrast, Ascl-1null mutants showed reduced neurogenesis for both vomeronasal and GnRH-1ns but less severe defects in OEC development. These observations suggest that Gli3 is critical for OEC development in the nasal mucosa and subsequent GnRH-1 neuronal migration. However, the nonoverlapping phenotypes between Ascl-1 and Gli3 mutants indicate that Ascl-1, while crucial for GnRH-1 neurogenesis, is not required for normal OEC development. Because Kallmann syndrome (KS) is characterized by abnormal GnRH-1ns migration, we examined whole-exome sequencing data from KS subjects. We identified and validated a GLI3 loss-of-function variant in a KS individual. These findings provide new insights into GnRH-1 and OECs development and demonstrate that human GLI3 mutations contribute to KS etiology.

SIGNIFICANCE STATEMENT The transcription factor Gli3 is necessary for correct development of the olfactory system. However, if Gli3 plays a role in controlling GnRH-1 neuronal development has not been addressed. We found that Gli3 loss-of-function compromises the onset of Ascl-1+ vomeronasal progenitors, formation of olfactory ensheathing cells in the nasal mucosa, and impairs GnRH-1 neuronal migration to the brain. By analyzing Ascl-1null mutants we dissociated the neurogenic defects observed in Gli3 mutants from lack of olfactory ensheathing cells in the nasal mucosa, moreover, we discovered that Ascl-1 is necessary for GnRH-1 ontogeny. Analyzing human whole-exome sequencing data, we identified a GLI3 loss-of-function variant in a KS individual. Our data suggest that GLI3 is a candidate gene contributing to KS etiology.

  • Ascl-1
  • Gli3
  • GnRH-1
  • Kallmann syndrome
  • olfactory ensheathing cells
  • vomeronasal sensory neurons

This is an open-access article distributed under the terms of the Creative Commons Attribution License Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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The Journal of Neuroscience: 40 (2)
Journal of Neuroscience
Vol. 40, Issue 2
8 Jan 2020
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Gli3 Regulates Vomeronasal Neurogenesis, Olfactory Ensheathing Cell Formation, and GnRH-1 Neuronal Migration
Ed Zandro M. Taroc, Ankana S. Naik, Jennifer M. Lin, Nicolas B. Peterson, David L. Keefe Jr., Elizabet Genis, Gabriele Fuchs, Ravikumar Balasubramanian, Paolo E. Forni
Journal of Neuroscience 8 January 2020, 40 (2) 311-326; DOI: 10.1523/JNEUROSCI.1977-19.2019

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Gli3 Regulates Vomeronasal Neurogenesis, Olfactory Ensheathing Cell Formation, and GnRH-1 Neuronal Migration
Ed Zandro M. Taroc, Ankana S. Naik, Jennifer M. Lin, Nicolas B. Peterson, David L. Keefe Jr., Elizabet Genis, Gabriele Fuchs, Ravikumar Balasubramanian, Paolo E. Forni
Journal of Neuroscience 8 January 2020, 40 (2) 311-326; DOI: 10.1523/JNEUROSCI.1977-19.2019
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Keywords

  • Ascl-1
  • Gli3
  • GnRH-1
  • Kallmann syndrome
  • olfactory ensheathing cells
  • vomeronasal sensory neurons

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