The Function And Mechanism Of Anaplastic Lymphoma Kinase (ALK) In The Development Of Mammalian Neocortex

Precise regulation of embryonic neurodevelopment is crucial for the structural organization and proper functioning of the adult mammalian brain.The key molecular machinery orchestrating this process remains unclear.Anaplastic lymphoma kinase(ALK)is a receptor-type protein tyrosine kinase that is highly,specifically and transiently expressed in the central nervous system during embryonic development.Small molecule ALK inhibitors are clinically used to treat numerous cancers,including neuroblastoma,yet little is known about ALK function in the mammalian brain development.In this study,we employed diffusion tensor imaging(DTI),behavioral tests,and immunohistochemistry to investigate the roles of ALK signaling in mice,human neural progenitor cells(hNPCs)and human cerebral organoids.We show that transient embryonic ALK inactivation caused long-lasting modifications to the adult brain,including abnormal neuronal connectivity,anxiety-like behaviors and cognitive impairment.Immunostaining analysis revealed significantly decreased neuronal proliferation,delayed neuronal migration and altered adult cortical organization after transient embryonic ALK inactivation.To correlate with human cortical development,we extended our studies to human cerebral organoids,and observed phenotypes consistent with those manifested in mice.Single-cell RNA sequencing(scRNA-seq)analysis revealed altered transcriptional profiles after ALK inactivation.Together,our findings demonstrate that ALK profoundly regulates cortical development by promoting proliferation,survival and migration of neuronal cells.Transient disruption of these processes at embryonic stage can impair neuronal connectivity and functions of the adult brain.