Left-right Locomotor Circuitry Depends on RhoA-driven Organization of the Neuroepithelium in the Developing Spinal Cord

Overview

Journal J Neurosci

Specialty Neurology

Date 2012 Jul 28

PMID 22836272

Citations 10

Authors

Kei-Ichi Katayama

Jennifer R Leslie

Richard A Lang

Yi Zheng

Yutaka Yoshida

Affiliations

Soon will be listed here.

Abstract

RhoA is a key regulator of cytoskeletal dynamics with a variety of effects on cellular processes. Loss of RhoA in neural progenitor cells disrupts adherens junctions and causes disorganization of the neuroepithelium in the developing nervous system. However, it remains essentially unknown how the loss of RhoA physiologically affects neural circuit formation. Here we show that proper neuroepithelial organization maintained by RhoA GTPase in both the ventral and dorsal spinal cord is critical for left-right locomotor behavior. We examined the roles of RhoA in the ventral and dorsal spinal cord by deleting the gene in neural progenitors using Olig2-Cre and Wnt1-Cre mice, respectively. RhoA-deleted neural progenitors in both mutants exhibit defects in the formation of apical adherens junctions and disorganization of the neuroepithelium. Consequently, the ventricular zone and lumen of the dysplastic region are lost, causing the left and right sides of the gray matter to be directly connected. Furthermore, the dysplastic region lacks ephrinB3 expression at the midline that is required for preventing EphA4-expressing corticospinal neurons and spinal interneurons from crossing the midline. As a result, aberrant neuronal projections are observed in that region. Finally, both RhoA mutants develop a rabbit-like hopping gait. These results demonstrate that RhoA functions to maintain neuroepithelial structures in the developing spinal cord and that proper organization of the neuroepithelium is required for appropriate left-right motor behavior.

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References

Dottori M, Hartley L, Galea M, Paxinos G, Polizzotto M, Kilpatrick T . EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc Natl Acad Sci U S A. 1998; 95(22):13248-53. PMC: 23772. DOI: 10.1073/pnas.95.22.13248. View

Yokoyama N, Romero M, Cowan C, Galvan P, Helmbacher F, Charnay P . Forward signaling mediated by ephrin-B3 prevents contralateral corticospinal axons from recrossing the spinal cord midline. Neuron. 2001; 29(1):85-97. DOI: 10.1016/s0896-6273(01)00182-9. View

Kobayashi K, Takahashi M, Matsushita N, Miyazaki J, Koike M, Yaginuma H . Survival of developing motor neurons mediated by Rho GTPase signaling pathway through Rho-kinase. J Neurosci. 2004; 24(14):3480-8. PMC: 6729735. DOI: 10.1523/JNEUROSCI.0295-04.2004. View

Chen J, Huang Y, Mazzoni E, Tan G, Zavadil J, Wichterle H . Mir-17-3p controls spinal neural progenitor patterning by regulating Olig2/Irx3 cross-repressive loop. Neuron. 2011; 69(4):721-35. PMC: 3062262. DOI: 10.1016/j.neuron.2011.01.014. View

Rossi J, Balthasar N, Olson D, Scott M, Berglund E, Lee C . Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. 2011; 13(2):195-204. PMC: 3033043. DOI: 10.1016/j.cmet.2011.01.010. View

Canty A, Murphy M . Molecular mechanisms of axon guidance in the developing corticospinal tract. Prog Neurobiol. 2008; 85(2):214-35. DOI: 10.1016/j.pneurobio.2008.02.001. View

Jessell T . Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat Rev Genet. 2001; 1(1):20-9. DOI: 10.1038/35049541. View

Chauhan B, Lou M, Zheng Y, Lang R . Balanced Rac1 and RhoA activities regulate cell shape and drive invagination morphogenesis in epithelia. Proc Natl Acad Sci U S A. 2011; 108(45):18289-94. PMC: 3215052. DOI: 10.1073/pnas.1108993108. View

Iwasato T, Katoh H, Nishimaru H, Ishikawa Y, Inoue H, Saito Y . Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling. Cell. 2007; 130(4):742-53. DOI: 10.1016/j.cell.2007.07.022. View

10.

Linseman D, Loucks F . Diverse roles of Rho family GTPases in neuronal development, survival, and death. Front Biosci. 2007; 13:657-76. DOI: 10.2741/2710. View

11.

Hsu W, Mirando A, Yu H . Manipulating gene activity in Wnt1-expressing precursors of neural epithelial and neural crest cells. Dev Dyn. 2009; 239(1):338-45. PMC: 2797833. DOI: 10.1002/dvdy.22044. View

12.

Wichterle H, Lieberam I, Porter J, Jessell T . Directed differentiation of embryonic stem cells into motor neurons. Cell. 2002; 110(3):385-97. DOI: 10.1016/s0092-8674(02)00835-8. View

13.

Restrepo C, Margaryan G, Borgius L, Lundfald L, Sargsyan D, Kiehn O . Change in the balance of excitatory and inhibitory midline fiber crossing as an explanation for the hopping phenotype in EphA4 knockout mice. Eur J Neurosci. 2011; 34(7):1102-12. DOI: 10.1111/j.1460-9568.2011.07838.x. View

14.

Leslie J, Imai F, Fukuhara K, Takegahara N, Rizvi T, Friedel R . Ectopic myelinating oligodendrocytes in the dorsal spinal cord as a consequence of altered semaphorin 6D signaling inhibit synapse formation. Development. 2011; 138(18):4085-95. PMC: 3160102. DOI: 10.1242/dev.066076. View

15.

Rousso D, Gaber Z, Wellik D, Morrisey E, Novitch B . Coordinated actions of the forkhead protein Foxp1 and Hox proteins in the columnar organization of spinal motor neurons. Neuron. 2008; 59(2):226-40. PMC: 2547125. DOI: 10.1016/j.neuron.2008.06.025. View

16.

Imondi R, Wideman C, Kaprielian Z . Complementary expression of transmembrane ephrins and their receptors in the mouse spinal cord: a possible role in constraining the orientation of longitudinally projecting axons. Development. 2000; 127(7):1397-410. DOI: 10.1242/dev.127.7.1397. View

17.

Dasen J, Jessell T . Hox networks and the origins of motor neuron diversity. Curr Top Dev Biol. 2009; 88:169-200. DOI: 10.1016/S0070-2153(09)88006-X. View

18.

Kullander K, Croll S, Zimmer M, Pan L, McClain J, Hughes V . Ephrin-B3 is the midline barrier that prevents corticospinal tract axons from recrossing, allowing for unilateral motor control. Genes Dev. 2001; 15(7):877-88. PMC: 312668. DOI: 10.1101/gad.868901. View

19.

Kullander K, Butt S, Lebret J, Lundfald L, Restrepo C, Rydstrom A . Role of EphA4 and EphrinB3 in local neuronal circuits that control walking. Science. 2003; 299(5614):1889-92. DOI: 10.1126/science.1079641. View

20.

Goulding M . Circuits controlling vertebrate locomotion: moving in a new direction. Nat Rev Neurosci. 2009; 10(7):507-18. PMC: 2847453. DOI: 10.1038/nrn2608. View