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 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.
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.
Isobel D
ID
Lawrenson
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Current address: Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
Danielle L
DL
Krebs
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Edmond M
EM
Linossi
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Jian-Guo
JG
Zhang
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.
Tamara J
TJ
McLennan
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.
Caitlin
C
Collin
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Helen M
HM
McRae
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.
Tatiana B
TB
Kolesnik
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Katrina
K
Koh
Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia.
Joanne M
JM
Britto
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Andrew J
AJ
Kueh
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Bilal N
BN
Sheikh
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Farrah
F
El-Saafin
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Nicos A
NA
Nicola
Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia.
Seong-Seng
SS
Tan
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Jeffrey J
JJ
Babon
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Sandra E
SE
Nicholson
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Warren S
WS
Alexander
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Tim
T
Thomas
Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Anne K
AK
Voss
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency* / Q000235:genetics
D015816:Cell Adhesion Molecules, Neuronal; C103773:Dab1 protein, mouse; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C506118:SOCS7 protein, mouse; C473086:Socs6 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases