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.
|State||Published - Jan 1 2018|
Bibliographical noteFunding Information:
Received October 13, 2017; accepted January 17, 2018; First published January 22, 2018. The authors declare no competing financial interests. Author contributions: T.J.H. and D.S.S. designed research; T.J.H., X.G., S.S., and M.M.L. performed research; T.J.H. and D.S.S. analyzed data; J.R.T. and J.L.T. contributed unpublished reagents/analytic tools; D.S.S. wrote the paper. This work was funded by National Institutes of Health Grants R01-NS056314 (to D.S.S.), R00-DA-032681 (to J.R.T.), and R01-NS089963 (to J.L.T.). J.L.T. is the incumbent of the SmartState Chair in Childhood Neurotherapeutics at the University of South Carolina. Acknowledgements: We thank Tia Davis for her help with mouse colony maintenance. Correspondence should be addressed to Deanna S. Smith, CLS 607, Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, E-mail: firstname.lastname@example.org. DOI:http://dx.doi.org/10.1523/ENEURO.0350-17.2018 Copyright © 2018 Hines et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
This work was funded by National Institutes of Health Grants R01-NS056314 (to D.S.S.), R00-DA-032681 (to J.R.T.), and R01-NS089963 (to J.L.T.). J.L.T. is the incumbent of the SmartState Chair in Childhood Neurotherapeutics at the University of South Carolina.
© 2018 Hines et al.
- Axonal transport
- Cytoplasmic dynein
- Knockout mouse
- Neurological disease
ASJC Scopus subject areas
- Neuroscience (all)