MRCKß links Dasm1 to actin rearrangements to promote dendrite development.
J Biol Chem
; 296: 100730, 2021.
Article
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| MEDLINE
| ID: mdl-33933448
ABSTRACT
Proper dendrite morphogenesis and synapse formation are essential for neuronal development and function. Dasm1, a member of the immunoglobulin superfamily, is known to promote dendrite outgrowth and excitatory synapse maturation in vitro. However, the in vivo function of Dasm1 in neuronal development and the underlying mechanisms are not well understood. To learn more, Dasm1 knockout mice were constructed and employed to confirm that Dasm1 regulates dendrite arborization and spine formation in vivo. We performed a yeast two-hybrid screen using Dasm1, revealing MRCKß as a putative partner; additional lines of evidence confirmed this interaction and identified cytoplasmic proline-rich region (823-947 aa) of Dasm1 and MRCKß self-activated kinase domain (CC1, 410-744 aa) as necessary and sufficient for binding. Using co-immunoprecipitation assay, autophosphorylation assay, and BS3 cross-linking assay, we show that Dasm1 binding triggers a change in MRCKß's conformation and subsequent dimerization, resulting in autophosphorylation and activation. Activated MRCKß in turn phosphorylates a class 2 regulatory myosin light chain, which leads to enhanced actin rearrangement, causing the dendrite outgrowth and spine formation observed before. Removal of Dasm1 in mice leads to behavioral abnormalities. Together, these results reveal a crucial molecular pathway mediating cell surface and intracellular signaling communication to regulate actin dynamics and neuronal development in the mammalian brain.
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MEDLINE
Asunto principal:
Inmunoglobulinas
/
Actinas
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Dendritas
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Proteínas del Tejido Nervioso
Límite:
Animals
Idioma:
En
Revista:
J Biol Chem
Año:
2021
Tipo del documento:
Article