Cortical Layer Inversion and Deregulation of Reelin Signaling in the Absence of SOCS6 and SOCS7
Mutations of the reelin gene cause severe defects in cerebral cortex development and profound intellectual impairment. While many aspects of the reelin signaling pathway have been identified, the molecular and ultimate cellular consequences of reelin signaling remain unknown. Specifically, it is unc...
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Published in | Cerebral cortex (New York, N.Y. 1991) Vol. 27; no. 1; pp. 576 - 588 |
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Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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01.01.2017
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Abstract | Mutations of the reelin gene cause severe defects in cerebral cortex development and profound intellectual impairment. While many aspects of the reelin signaling pathway have been identified, the molecular and ultimate cellular consequences of reelin signaling remain unknown. Specifically, it is unclear if termination of reelin signaling is as important for normal cortical neuron migration as activation of reelin signaling. Using mice that are single or double deficient, we discovered that combined loss of the suppressors of cytokine signaling, SOCS6 and SOCS7, recapitulated the cortical layer inversion seen in mice lacking reelin and led to a dramatic increase in the reelin signaling molecule disabled (DAB1) in the cortex. The SRC homology domains of SOCS6 and SOCS7 bound DAB1 ex vivo. Mutation of DAB1 greatly diminished binding and protected from degradation by SOCS6. Phosphorylated DAB1 was elevated in cortical neurons in the absence of SOCS6 and SOCS7. Thus, constitutive activation of reelin signaling was observed to be equally detrimental as lack of activation. We hypothesize that, by terminating reelin signaling, SOCS6 and SOCS7 may allow new cycles of reelin signaling to occur and that these may be essential for cortical neuron migration. |
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AbstractList | Mutations of the reelin gene cause severe defects in cerebral cortex development and profound intellectual impairment. While many aspects of the reelin signaling pathway have been identified, the molecular and ultimate cellular consequences of reelin signaling remain unknown. Specifically, it is unclear if termination of reelin signaling is as important for normal cortical neuron migration as activation of reelin signaling. Using mice that are single or double deficient, we discovered that combined loss of the suppressors of cytokine signaling, SOCS6 and SOCS7, recapitulated the cortical layer inversion seen in mice lacking reelin and led to a dramatic increase in the reelin signaling molecule disabled (DAB1) in the cortex. The SRC homology domains of SOCS6 and SOCS7 bound DAB1 ex vivo. Mutation of DAB1 greatly diminished binding and protected from degradation by SOCS6. Phosphorylated DAB1 was elevated in cortical neurons in the absence of SOCS6 and SOCS7. Thus, constitutive activation of reelin signaling was observed to be equally detrimental as lack of activation. We hypothesize that, by terminating reelin signaling, SOCS6 and SOCS7 may allow new cycles of reelin signaling to occur and that these may be essential for cortical neuron migration. |
Author | Tan, Seong-Seng Thomas, Tim Linossi, Edmond M Kueh, Andrew J Nicholson, Sandra E Voss, Anne K Nicola, Nicos A Lawrenson, Isobel D Kolesnik, Tatiana B Alexander, Warren S Krebs, Danielle L Britto, Joanne M Koh, Katrina El-Saafin, Farrah Zhang, Jian-Guo Babon, Jeffrey J Collin, Caitlin McRae, Helen M Sheikh, Bilal N McLennan, Tamara J |
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SubjectTerms | Animals Cell Adhesion Molecules, Neuronal - genetics Cell Adhesion Molecules, Neuronal - metabolism Cell Movement - physiology Cerebral Cortex - embryology Cerebral Cortex - metabolism Cerebral Cortex - pathology Extracellular Matrix Proteins - genetics Extracellular Matrix Proteins - metabolism HEK293 Cells Humans Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Neurons - metabolism Phosphorylation Serine Endopeptidases - genetics Serine Endopeptidases - metabolism Suppressor of Cytokine Signaling Proteins - deficiency Suppressor of Cytokine Signaling Proteins - genetics |
Title | Cortical Layer Inversion and Deregulation of Reelin Signaling in the Absence of SOCS6 and SOCS7 |
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