Cajal-Retzius cells instruct neuronal migration by coincidence signaling between secreted and contact-dependent guidance cues.
Cajal-Retzius (CR) cells are a transient cell population of the CNS that is critical for brain development. In the neocortex, CR cells secrete reelin to instruct the radial migration of projection neurons. It has remained unexplored, however, whether CR cells provide additional molecular cues important for brain development. Here, we show that CR cells express the immunoglobulin-like adhesion molecule nectin1, whereas neocortical projection neurons express its preferred binding partner, nectin3. We demonstrate that nectin1- and nectin3-mediated interactions between CR cells and migrating neurons are critical for radial migration. Furthermore, reelin signaling to Rap1 promotes neuronal Cdh2 function via nectin3 and afadin, thus directing the broadly expressed homophilic cell adhesion molecule Cdh2 toward mediating heterotypic cell-cell interactions between neurons and CR cells. Our findings identify nectins and afadin as components of the reelin signaling pathway and demonstrate that coincidence signaling between CR cell-derived secreted and short-range guidance cues direct neuronal migration.
Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Cristina
C
Gil-Sanz
Santos J
SJ
Franco
Isabel
I
Martinez-Garay
Ana
A
Espinosa
Sarah
S
Harkins-Perry
Ulrich
U
Müller
D000367:Age Factors; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002450:Cell Communication / Q000235:genetics; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D000089622:Doublecortin Domain Proteins; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics; D000075983:Nectins; D019579:Neocortex / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics; D011506:Proteins; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated; D000091042:Reelin Protein; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D060509:Wnt3A Protein / Q000235:genetics
D015820:Cadherins; C489083:Cdh2 protein, mouse; D015815:Cell Adhesion Molecules; D000089622:Doublecortin Domain Proteins; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; C000619015:Nectin1 protein, mouse; C000619017:Nectin3 protein, mouse; D000075983:Nectins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D011506:Proteins; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; D000091042:Reelin Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C108835:afadin; C000717128:Reln protein, mouse