Dab1-flox Mouse

Dab1, also known as Disabled 1, is an intracellular adaptor protein essential for brain formation during development. It is a key component of the Reelin-Dab1 signaling pathway, which regulates neuron migrations in various brain regions, as well as learning and memory in adults [8]. Extracellular Reelin binds to cell surface receptors, leading to the phosphorylation of Dab1, which then affects several downstream pathways crucial for neuronal migration, dendrite development, and synapse formation [9].

Loss-of-function mutations in Dab1 have been studied in mouse models. Heterozygous yotari mice with a single autosomal recessive yotari mutation of Dab1 exhibited a thinner neocortical layer 1 and abnormal splitting of the CA1 pyramidal cell layer in the caudo-dorsal hippocampus, suggesting unique dependencies on Dab1 gene dosage in different brain regions for neuronal migration and positioning [3]. In Dab1-deficient deep layer neurons, they prevent Dab1-deficient superficial layer neurons from entering the cortical plate, reflecting a non-cell-autonomous function of Dab1 [4]. Also, in the hippocampal formation, disruption of lamination in the CA1, CA3, and dentate gyrus was different in Dab1-deficient mice, indicating that the morphogenesis in these hippocampal subdivisions involves different developmental mechanisms related to Dab1 function [7].

In summary, Dab1 is vital for normal brain development, playing key roles in neuronal migration, positioning, and the morphogenesis of different brain regions. Mouse models with Dab1 loss-of-function mutations have provided insights into its functions in normal development and have implications for understanding diseases such as medulloblastoma metastasis and sporadic Alzheimer's disease, where disruption of the ApoER2-Dab1 pathway may drive pTau-associated neurodegeneration [2,1,5,6].