Abstract
Background Core planar cell polarity gene Celsr3 (Cadherin EGF Laminin Seven Pass Receptor), the mammalian orthologs of Drosophila Flamingo/starry night, encode proteins of the cadherin superfamily. Celsr3 plays a critical role in forebrain wiring, particularly the development of anterior commissure (AC) and the internal capsule (IC). Previous work showed that inactivation of Celsr3 in hippocampal projection neurons perturbed intrinsic hippocampal wiring and mutant mice showed impaired learning and memory. However, the effects of Celsr3 inactivation on hippocampal efferent fibers, synaptogenesis and adult neurogenesis are still not clear.
Method We studied Emx1-Cre; Celsr3f/- (abbreviated as Celsr3|Emx1) mutant mice as the experimental group, processed histological staining and electron microscopy analysis.
Result Inactivation of Celsr3 in hippocampal projection neurons impaired efferent fiber projections, whereas afferent fibers from entorhinal cortex were unaffected. In addition, it resulted in incomplete maturation of pyramidal cell dendrites and synaptogenesis, and increased adult neurogenesis in the dentate gyrus.
Conclusion Hippocampal efferent pathways and synapse formation are defective in Celsr3|Emx1 mutant mice, while adult neurogenesis in the dentate gyrus is increased.
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References
Femenía T, Gómez-Galán M, Lindskog M, Magara S. Dysfunctional hippocampal activity affects emotion and cognition in mood disorders. Brain Res. 2012 Oct 2;1476:58-70. doi: 10.1016/j.brainres.2012.03.053.
Subramanian L, Tole S. Mechanisms underlying the specification, positional regulation, and function of the cortical hem. Cereb Cortex. 2009 Jul;19 Suppl 1:i90-5. doi: 10.1093/cercor/bhp031.
Grove EA, Tole S. Patterning events and specification signals in the developing hippocampus. Cereb Cortex. 1999 Sep;9(6):551-61. doi: 10.1093/cercor/9.6.551.
Patton PE, McNaughton B. Connection matrix of the hippocampal formation: I. The dentate gyrus. Hippocampus. 1995;5(4):245-86. doi: 10.1002/hipo.
Förster E, Zhao S, Frotscher M. Laminating the hippocampus. Nat Rev Neurosci. 2006 Apr;7(4):259-67. doi: 10.1038/nrn1882.
Sørensen KE. The connections of the hippocampal region. New observations on efferent connections in the guinea pig, and their functional implications. Acta Neurol Scand. 1985 Dec;72(6):550-60. doi: 10.1111/j.1600-0404.1985.tb00914.x.
Witter MP, Amaral DG. Hippocampal formation. In: Paxinos G, editor. The Rat Nervous System. London: Elsevier; 2004. p. 635-704.
van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature. 2002 Feb 28;415(6875):1030-4. doi: 10.1038/4151030a.
Kheirbek MA, Klemenhagen KC, Sahay A, Hen R. Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat Neurosci. 2012 Dec;15(12):1613-20. doi: 10.1038/nn.3262.
Tissir F, Goffinet AM. Shaping the nervous system: role of the core planar cell polarity genes. Nat Rev Neurosci. 2013 Aug;14(8):525-35. doi: 10.1038/nrn3525.
Sasselli V, Boesmans W, Vanden Berghe P, Tissir F, Goffinet AM, Pachnis V. Planar cell polarity genes control the connectivity of enteric neurons. J Clin Invest. 2013 Apr;123(4):1763-72. doi: 10.1172/JCI66759.
Wang Y, Nathans J. Tissue/planar cell polarity in vertebrates: new insights and new questions. Development. 2007 Feb;134(4):647-58. doi: 10.1242/dev.02772.
Wang Y, Thekdi N, Smallwood PM, Macke JP, Nathans J. Frizzled-3 is required for the development of major fiber tracts in the rostral CNS. J Neurosci. 2002 Oct 1;22(19):8563-73. doi: 10.1523/JNEUROSCI.22-19-08563.2002.
Zhou L, Bar I, Achouri Y, Campbell K, De Backer O, Hebert JM, Jones K, Kessaris N, de Rouvroit CL, O'Leary D, Richardson WD, Goffinet AM, Tissir F. Early forebrain wiring: genetic dissection using conditional Celsr3 mutant mice. Science. 2008 May 16;320(5878):946-9. doi: 10.1126/science.1155244.
Tissir F, Bar I, Jossin Y, De Backer O, Goffinet AM. Protocadherin Celsr3 is crucial in axonal tract development. Nat Neurosci. 2005 Apr;8(4):451-7. doi: 10.1038/nn1428. Epub 2005 Mar 20. Erratum in: Nat Neurosci. 2006 Jan;9(1):147. De Backer, Olivier [added].
Qin J, Wang M, Zhao T, Xiao X, Li X, Yang J, Yi L, Goffinet AM, Qu Y, Zhou L. Early Forebrain Neurons and Scaffold Fibers in Human Embryos. Cereb Cortex. 2020 Mar 14;30(3):913-928. doi: 10.1093/cercor/bhz136.
Gorski JA, Talley T, Qiu M, Puelles L, Rubenstein JL, Jones KR. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J Neurosci. 2002 Aug 1;22(15):6309-14. doi: 10.1523/JNEUROSCI.22-15-06309.2002.
van Groen T, Miettinen P, Kadish I. The entorhinal cortex of the mouse: organization of the projection to the hippocampal formation. Hippocampus. 2003;13(1):133-49. doi: 10.1002/hipo.10037.
Adelmann G, Deller T, Frotscher M. Organization of identified fiber tracts in the rat fimbria-fornix: an anterograde tracing and electron microscopic study. Anat Embryol (Berl). 1996 May;193(5):481-93. doi: 10.1007/BF00185879.
Witter MP. Connections of the subiculum of the rat: topography in relation to columnar and laminar organization. Behav Brain Res. 2006 Nov 11;174(2):251-64. doi: 10.1016/j.bbr.2006.06.022.
Kee N, Sivalingam S, Boonstra R, Wojtowicz JM. The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis. J Neurosci Methods. 2002 Mar 30;115(1):97-105. doi: 10.1016/s0165-0270(02)00007-9.
Sahay A, Scobie KN, Hill AS, O'Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, Hen R. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature. 2011 Apr 28;472(7344):466-70. doi: 10.1038/nature09817.
Feng J, Xu Y, Wang M, Ruan Y, So KF, Tissir F, Goffinet A, Zhou L. A role for atypical cadherin Celsr3 in hippocampal maturation and connectivity. J Neurosci. 2012 Oct 3;32(40):13729-43. doi: 10.1523/JNEUROSCI.1965-12.2012.
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