An essential postdevelopmental role for Lis1 in Mice

Timothy J. Hines, Xu Gao, Subhshri Sahu, Meghann M. Lange, Jill R. Turner, Jeffery L. Twiss, Deanna S. Smith

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


LIS1 mutations cause lissencephaly (LIS), a severe developmental brain malformation. Much less is known about its role in the mature nervous system. LIS1 regulates the microtubule motor cytoplasmic dynein 1 (dynein), and as LIS1 and dynein are both expressed in the adult nervous system, Lis1 could potentially regulate dyneindependent processes such as axonal transport. We therefore knocked out Lis1 in adult mice using tamoxifeninduced, Cre-ER-mediated recombination. When an actin promoter was used to drive Cre-ER expression (Act-Cre-ER), heterozygous Lis1 knockout (KO) caused no obvious change in viability or behavior, despite evidence of widespread recombination by a Cre reporter three weeks after tamoxifen exposure. In contrast, homozygous Lis1 KO caused the rapid onset of neurological symptoms in both male and female mice. One tamoxifen-dosing regimen caused prominent recombination in the midbrain/hindbrain, PNS, and cardiac/skeletal muscle within a week; these mice developed severe symptoms in that time frame and were killed. A different tamoxifen regimen resulted in delayed recombination in midbrain/hindbrain, but not in other tissues, and also delayed the onset of symptoms. This indicates that Lis1 loss in the midbrain/hindbrain causes the severe phenotype. In support of this, brainstem regions known to house cardiorespiratory centers showed signs of axonal dysfunction in KO animals. Transport defects, neurofilament (NF) alterations, and varicosities were observed in axons in cultured DRG neurons from KO animals. Because no symptoms were observed when a cardiac specific Cre-ER promoter was used, we propose a vital role for Lis1 in autonomic neurons and implicate defective axonal transport in the KO phenotype.

Original languageEnglish
Article numbere0350-17.2018
Issue number1
StatePublished - Jan 1 2018

Bibliographical note

Publisher Copyright:
© 2018 Hines et al.


  • Axonal transport
  • Brainstem
  • Cytoplasmic dynein
  • Knockout mouse
  • Lis1
  • Neurological disease

ASJC Scopus subject areas

  • General Neuroscience


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