MYRF: A unique transmembrane transcription factor‐ from proteolytic self‐processing to its multifaceted roles in animal development

The Myelin Regulator Factor (MYRF) is a master regulator governing myelin formation and maintenance in the central nervous system. The conservation of MYRF across metazoans and its broad tissue expression suggest it has functions extending beyond the well‐established role in myelination. Loss of MYRF results in developmental lethality in both invertebrates and vertebrates, and MYRF haploinsufficiency in humans causes MYRF‐related Cardiac Urogenital Syndrome, underscoring its importance in animal development; however, these mechanisms are largely unexplored. MYRF, an unconventional transcription factor, begins embedded in the membrane and undergoes intramolecular chaperone mediated trimerization, which triggers self‐cleavage, allowing its N‐terminal segment with an Ig‐fold DNA‐binding domain to enter the nucleus for transcriptional regulation. Recent research suggests developmental regulation of cleavage, yet the mechanisms remain enigmatic. While some parts of MYRF's structure have been elucidated, others remain obscure, leaving questions about how these motifs are linked to its intricate processing and function. MYRF is a unique transmembrane transcription factor. It is initially inserted in the membrane, and then undergoes trimerization via its intramolecular chaperone domain (ICA); the process leads to self‐cleavage, releasing the N‐terminal MYRF in a trimeric form, which then enters the nucleus for gene regulation. MYRF is essential for the formation and maintenance of myelination in the central nervous system (CNS). It is also crucial for animal development. Haploinsufficiency of MYRF in humans causes a developmental disorder known as MYRF‐related cardiac urogenital syndrome.