Abstract
Oligodendroglial cells are a type of glial cell in the central nervous system (CNS) that wrap neuronal axons with differentiated plasma membranes known as myelin sheaths. While the physiological functions of oligodendrocytes, such as generating saltatory conduction and protecting neuronal axons, are well understood, the physiological and/or pathophysiological molecular mechanisms governing their differentiation before myelination remain unclear. In this study, we describe for the first time that claudin-11, a protein associated with hypomyelinating leukodystrophy 22 (HLD22), interacts with shroom-2, a presumable adaptor protein containing the PSD95, DLG1, and ZO-1 (PDZ) domain. Knockdown of claudin-11 using specific siRNA resulted in a decrease in morphological changes and marker proteins in the FBD-102b oligodendroglial model undergoing differentiation. Transfection of the C-terminal PDZ ligand sequence of claudin-11, which was found to interact with the PDZ domain of shroom-2, also reduced these phenotypic changes. The HLD22-associated mutated sequence in claudin-11 failed to interact with the PDZ domain of shroom-2. Furthermore, knockdown of shroom-2 or transfection of the PDZ domain of shroom-2, which is involved in the interaction with claudin-11, resulted in decreased morphological changes and marker protein expression. These changes were linked to the phosphorylation states of Akt kinase, a key signaling molecule in oligodendroglial cell differentiation and myelination. These results suggest that the interaction between claudin-11 and shroom-2 plays a key role in shaping cell morphology, providing insights into the molecular mechanisms underlying oligodendroglial differentiation before myelination, as well as potential pathological mechanisms associated with HLD22 at the molecular and cellular levels.