1. Developmental Biology

Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1

  1. Edward Kim
  2. Yuan Wang
  3. Sun-Jung Kim
  4. Miriam Bornhorst
  5. Emmanuelle S Jecrois
  6. Todd E Anthony
  7. Chenran Wang
  8. Yi E Li
  9. Jun-Lin Guan
  10. Geoffrey G Murphy
  11. Yuan Zhu  Is a corresponding author
  1. University of Michigan Medical School, United States
  2. Children's National Medical Center, United States
  3. Rockefeller University, United States
  4. University of Cincinnati College of Medicine, United States
https://doi.org/10.7554/eLife.05151
Share this article
Cite this article
  1. Edward Kim
  2. Yuan Wang
  3. Sun-Jung Kim
  4. Miriam Bornhorst
  5. Emmanuelle S Jecrois
  6. Todd E Anthony
  7. Chenran Wang
  8. Yi E Li
  9. Jun-Lin Guan
  10. Geoffrey G Murphy
  11. Yuan Zhu
(2014)
Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
eLife 3:e05151.
https://doi.org/10.7554/eLife.05151
  2. Download BibTeX
  3. Download .RIS

Abstract

Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities.

Article and author information

Author details

  1. Edward Kim

    Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Yuan Wang

    Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Sun-Jung Kim

    Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Miriam Bornhorst

    Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Emmanuelle S Jecrois

    Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Todd E Anthony

    Laboratory of Molecular Biology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Chenran Wang

    Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Yi E Li

    Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Jun-Lin Guan

    Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Geoffrey G Murphy

    Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Yuan Zhu

    Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
    For correspondence
    yzhu@childrensnational.org
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Duojia Pan, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, United States

Ethics

Animal experimentation: All mice in this study were cared for according to the guidelines that were approved by the Animal Care and Use Committees of the University of Michigan at Ann Arbor, MI and the Children's National Medical Center in Washington, DC. The approved protocol number at the University of Michigan is PRO00004481. The project (ID# 30001543) was approved by the IACUC (Protocol#: 309-13-09) of the Children's National Medical Center at Washington.

Version history

  1. Received: October 13, 2014
  2. Accepted: December 22, 2014
  3. Accepted Manuscript published: December 23, 2014 (version 1)
  4. Version of Record published: January 21, 2015 (version 2)

Copyright

© 2014, Kim et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,276
    views
  • 408
    downloads
  • 20
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Edward Kim
  2. Yuan Wang
  3. Sun-Jung Kim
  4. Miriam Bornhorst
  5. Emmanuelle S Jecrois
  6. Todd E Anthony
  7. Chenran Wang
  8. Yi E Li
  9. Jun-Lin Guan
  10. Geoffrey G Murphy
  11. Yuan Zhu
(2014)
Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
eLife 3:e05151.
https://doi.org/10.7554/eLife.05151

Share this article

https://doi.org/10.7554/eLife.05151

Categories and tags

Research organism

Further reading

    1. Developmental Biology
    2. Structural Biology and Molecular Biophysics

    Deep learning insights into the architecture of the mammalian egg-sperm fusion synapse

    Arne Elofsson, Ling Han ... Luca Jovine
    Research Article

    A crucial event in sexual reproduction is when haploid sperm and egg fuse to form a new diploid organism at fertilization. In mammals, direct interaction between egg JUNO and sperm IZUMO1 mediates gamete membrane adhesion, yet their role in fusion remains enigmatic. We used AlphaFold to predict the structure of other extracellular proteins essential for fertilization to determine if they could form a complex that may mediate fusion. We first identified TMEM81, whose gene is expressed by mouse and human spermatids, as a protein having structural homologies with both IZUMO1 and another sperm molecule essential for gamete fusion, SPACA6. Using a set of proteins known to be important for fertilization and TMEM81, we then systematically searched for predicted binary interactions using an unguided approach and identified a pentameric complex involving sperm IZUMO1, SPACA6, TMEM81 and egg JUNO, CD9. This complex is structurally consistent with both the expected topology on opposing gamete membranes and the location of predicted N-glycans not modeled by AlphaFold-Multimer, suggesting that its components could organize into a synapse-like assembly at the point of fusion. Finally, the structural modeling approach described here could be more generally useful to gain insights into transient protein complexes difficult to detect experimentally.

    1. Developmental Biology

    Inhibitory G proteins play multiple roles to polarize sensory hair cell morphogenesis

    Amandine Jarysta, Abigail LD Tadenev ... Basile Tarchini
    Research Article

    Inhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and for hearing. The extent and nature of their actual contributions remains unclear, however, as previous studies did not investigate all GNAI proteins and included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3, and GNAO proteins, but may also induce unrelated defects. Here, we directly and systematically determine the role(s) of each individual GNAI protein in mouse auditory hair cells. GNAI2 and GNAI3 are similarly polarized at the hair cell apex with their binding partner G protein signaling modulator 2 (GPSM2), whereas GNAI1 and GNAO are not detected. In Gnai3 mutants, GNAI2 progressively fails to fully occupy the sub-cellular compartments where GNAI3 is missing. In contrast, GNAI3 can fully compensate for the loss of GNAI2 and is essential for hair bundle morphogenesis and auditory function. Simultaneous inactivation of Gnai2 and Gnai3 recapitulates for the first time two distinct types of defects only observed so far with pertussis toxin: (1) a delay or failure of the basal body to migrate off-center in prospective hair cells, and (2) a reversal in the orientation of some hair cell types. We conclude that GNAI proteins are critical for hair cells to break planar symmetry and to orient properly before GNAI2/3 regulate hair bundle morphogenesis with GPSM2.

    1. Computational and Systems Biology
    2. Developmental Biology

    A logic-incorporated gene regulatory network deciphers principles in cell fate decisions

    Gang Xue, Xiaoyi Zhang ... Zhiyuan Li
    Research Article

    Organisms utilize gene regulatory networks (GRN) to make fate decisions, but the regulatory mechanisms of transcription factors (TF) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision-making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top-down fate-decision studies and a practical approach to the taxonomy of cell fate decisions.