The Wingless (Wnt) signaling path is among the key regulators of OL advancement and myelin regrowth. In certain diseased conditions and brain injury, its levels rise in the white matter, which hinders myelin production by requiring oligodendroctyes to remain in a “stalled/quiescent state”.
A couple of years back, Dr. Lee and others discovered that a glial protein, Daam2 prevents the distinction of oligodendrocytes during advancement as well as myelin regeneration and repair work. Up until now precise mechanisms underlying this procedure have remained a secret.
To comprehend how Daam2 hinders myelination, the team first needed to figure out the regulation of Daam2 itself. Utilizing biochemical methods, they found 2 amino acid residues (Ser704 and Thr705) of Daam2 protein undergo phosphorylation– a common post-translational regulative system that turns on or off the activity of the proteins.
To check out if Daam2 phosphorylation impacted the progression of OL lineage, they examined differentially revealed genes (DEGs) in wild-type and mutant animals whose Daam2 is constitutively phosphorylated. DEGs downregulated in the mutant OLs were enriched in genes included in lipid/cholesterol metabolic process whereas DEGs upregulated in the mutant OLs were associated with multiple signaling processes, including the Wnt pathway.
Given that Daam2 is a recognized favorable modulator of canonical Wnt signaling, they took a look at whether these DEGs was because of perturbations in Wnt signaling. They carried out a thorough developmental stage-specific analysis which revealed dynamic modifications in the equipment and function of Wnt/ β-catenin signaling in early versus late phases of OL advancement, and established that this signaling pathway is affected by Daam2 phosphorylation.
” Intriguingly, we found Daam2 phosphorylation differentially impacts distinct stages of oligodendrocyte development– in early stages, it speeds up the conversion of precursor OLs to glial cells however in later phases, it slows down their maturation and their capability to produce myelin,” Dr. Lee said.
To identify the kinase( s) accountable for Daam2 phosphorylation, they conducted a theme analysis which discovered CK2, a Wnt/ β-catenin signaling Ser/Thr kinase that was also one of the prospects in their genetic and biochemical screen. They further validated that its catalytic subunit, CK2α, engaged with Daam2 in lab-cultured OLs and likewise phosphorylated it. Both Daam2 and CK2α were sequentially upregulated in a manner that was concomitant with the progression of OL lineage. Utilizing in vitro cultured OLs and in vivo mouse models, they discovered compelling proof suggesting that CK2α promotes OL distinction by phosphorylating Daam2.
Further studies utilizing an animal design of neonatal hypoxic injury model revealed an advantageous role for CK2α-mediated Daam2 phosphorylation. They discovered that it plays a protective role in behavioral and developmental recovery after neonatal hypoxia, a form of brain injury seen in spastic paralysis and other conditions, and furthermore, it facilitates remyelination after white matter injury in adult animals.
Together, these findings have determined an unique regulative node in the Wnt path that regulates stage-specific oligodendrocyte advancement and offers insights into a new biological mechanism to regenerate myelin.
” This study opens exciting restorative avenues we might develop in the future to repair and restore myelin, which has the possible to relieve and deal with a number of neurological that are presently untreatable,” Dr. Lee said.
Reference: “Daam2 phosphorylation by CK2α adversely regulates Wnt activity throughout white matter advancement and injury” by Chih-Yen Wang, Zhongyuan Zuo, Juyeon Jo, Kyoung In Kim, Christine Madamba, Qi Ye, Sung Yun Jung, Hugo J. Bellen and Hyun Kyoung Lee, 22 August 2023, Proceedings of the National Academy of Sciences.DOI: 10.1073/ pnas.2304112120.
The first author, Chih-Yen Wang is now an assistant professor in the National Cheng Kung University. Others involved in the research study were Zhongyuan Zuo, Juyeon Jo, Kyoung In Kim, Christine Madamba, Qi Ye, Sung Yun Jung, and Hugo J. Bellen. They are connected with one or more of the following organizations: Baylor College of Medicine and Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital. This work was supported by grants from NIH/NINDS, the National Multiple Sclerosis Society, the Cynthia and Anthony G. Petrello Endowment, and the Mark A. Wallace Endowment, the Eunice Kennedy Shriver National Institute of Child Health & & Human Development of the National Institutes of Health for the BCM IDDRC Neurobehavior and Neurovisualization Cores. GERM core at Baylor College of Medicine helped with mouse line generation, scRNA-sequencing was partially supported by the SCG core and GARP core.
Scientists have actually found a new biological system involving Daam2 protein and CK2α kinase that regulates myelin repair work and regrowth. This study has ramifications for treating neurological diseases like multiple sclerosis and spastic paralysis.
A study led by Dr. Hyun Kyoung Lee, associate teacher at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital, has actually identified a formerly unidentified biological system for fixing and regenerating myelin. Myelin is the insulating layer around nerve fibers that is important for the fast and exact transmission of neural signals.
The Duncan NRI team found unique roles for the Dishevelled involved activator of morphogenesis 2 (Daam2) protein and CK2α kinase in controling myelin repair and regrowth. The research study was just recently published in the Proceedings of the National Academy of Science.
Myelin is produced by a kind of glial precursor cells called oligodendrocytes (OLs) which are among the most various cells in the nerve system. Damage or loss of myelin sheath is the hallmark of various neurological diseases in adults (e.g. numerous sclerosis) and infants (e.g. cerebral palsy) and prevails after brain injuries.
They even more confirmed that its catalytic subunit, CK2α, engaged with Daam2 in lab-cultured OLs and likewise phosphorylated it. Both Daam2 and CK2α were sequentially upregulated in a manner that was concomitant with the progression of OL family tree. The very first author, Chih-Yen Wang is now an assistant professor in the National Cheng Kung University. Others involved in the research study were Zhongyuan Zuo, Juyeon Jo, Kyoung In Kim, Christine Madamba, Qi Ye, Sung Yun Jung, and Hugo J. Bellen. They are connected with one or more of the following organizations: Baylor College of Medicine and Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital.
