In a study that appears in the journal Developmental Cell, Deneen and Lee describe the role of the protein Daam2 as playing an accessory, yet fundamental, part in canonical Wnt signaling during spinal cord development.
The Wnt signaling pathway is comprised of a network of proteins that function in concert to control several aspects of embryonic and tissue-specific development. Additionally, Wnt signaling, and dysregulation of its associated proteins has been implicated in a multitude of cancers and degenerative diseases.
“Wnt signaling is a complex process, with lots of “moving parts.” While we generally understand the net output of the signaling pathway, we don’t fully understand the dynamics of these moving parts and how they coalesce into active signaling. Daam2’s function had also not been categorized until now,” said Deneen. “Our findings show how Daam2 acts within this process, and in doing so, we were able to decipher the interrelationships between it and some of these core moving parts.”
Daam2 works with other proteins
Working in the laboratory, Lee was able to overexpress and knockdown Daam2 within the spinal cord. She found that Daam2 alone does not activate Wnt signaling.
“It works in combination with other proteins and acts on the core components, stabilizing them, which serves to amplify the signal so it can reach its target and generate the appropriate cellular output,” Lee said.
It is required for dorsal progenitor identities – progenitor cells differentiate into specific types of cell, in the spinal cord these populations generate distinct sub-types of neurons. Daam2 is also needed to potentiate Wnt ligand activation and does so by promoting the clustering of Wnt receptor complexes (Ligands are molecules that bind to other molecular complexes during development.)
“Daam2 is not part of the core components of the Wnt receptor complex, but if you remove it, the whole process falls apart, and consequently the spinal cord does not properly develop,” Deneen added.
Daam2 crucial for tissue development
While Deneen and Lee studied the developmental process in only spinal cord formation, they are confident, with more studies, these findings can be extended to other tissues and diseases where Wnt signaling is present.
“This is really a fundamental discovery, it is applicable to the spinal cord and brain in adults and the embryo, but also throughout the body because Wnt signaling is crucial for the development of several tissues and organ systems,” Deneen said. “Moreover, this signaling pathway has been implicated in many human tumors and several degenerative diseases. This raises the translational question: Is Daam2 influencing Wnt signaling in these human diseases in a similar way? Understanding how it operates will aid our search for these answers both inside and outside the CNS.”
Funding for this study came from the V Foundation for Cancer Research and the National Institutes of Health.
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