Cortical Layer Inversion and Deregulation of Reelin Signaling in the Absence of SOCS6 and SOCS7

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.

Importance and usage of chromosomal microarray analysis in diagnosing intellectual disability, global developmental delay, and autism; and discovering new loci for these disorders

“…Although this gene is deleted in our patient, he is not yet obese. Even though SOCS6 and SOCS7 have been reported to be necessary for cortical neuron migration [ 14 ], there was no evidence of migration defect in the MRI of our patient. The other gene in the deletion region in case 17, which may be important for ASD/ID, is CBLN2.…”

Circular RNA circ_103820 suppresses lung cancer tumorigenesis by sponging miR-200b-3p to release LATS2 and SOCS6

“…Studies have demonstrated the inhibitory effect of LATS2 expression in a variety of cancers 29,30 . SOCS6 is a member of the SOCS family and is mainly involved in the negative regulation of receptor tyrosine protein kinase 31 . SOCS6 is a vital factor for normal cell growth and can act as a tumor suppressor gene in a variety of cancers 32,33 .…”

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation

“…This rapid downregulation of the signal is necessary for a correct organization of the CP. Ablation of Cul5, Rbx2 or SOCS7 in migrating neurons results in the accumulation of Dab1 protein and a cortical layering defect [ 151 , 152 , 153 ]. The overexpression of a stabilized mutant Dab1, resistant to Cul5-dependent degradation, causes a similar phenotype [ 154 ].…”