MACF1 (microtubule actin crosslinking factor 1) is a versatile spectraplakin that serves as a critical cytoskeletal organizer, crosslinking F-actin filaments to microtubules and other cytoskeletal proteins 1. In the nervous system, MACF1 is essential for neurite outgrowth, neuronal migration, and axon guidance during brain development 2. The protein contains multiple functional domains including a GAR domain that binds microtubules and EF-hand domains; heterozygous missense variants affecting zinc-binding residues in these domains cause a distinctive lissencephaly with complex brainstem malformation characterized by absent pontine crossing fibers 34. MACF1 regulates focal adhesion dynamics and cell migration through interaction with CAMSAP3 at microtubule minus-ends 5. Beyond neurodevelopment, MACF1 participates in Wnt/β-catenin signaling and has been implicated in hepatocellular carcinoma metastasis, where it promotes epithelial-mesenchymal transition through β-catenin pathway activation 6. Loss-of-function studies reveal MACF1's importance in skin integrity, bone formation, and colonic permeability 5. Dysregulation or mutation of MACF1 associates with schizophrenia, Parkinson's disease, myopathy, and congenital myasthenic syndrome 27. Bi-allelic MACF1 variants suggest a complex neurodevelopmental syndrome affecting central and peripheral nervous systems 4.