The transient external granular layer in human foetal cerebellum: insights into neurogenesis, genetic regulation, and developmental disorders

The external granular layer (EGL) is a transient yet crucial layer for the formation of cerebellar cortex. Genetic mechanisms, including the sonic hedgehog (SHH) pathway is key to the proliferation of granule cell progenitors (GCPs), and disruptions in this process can lead to cerebellar disorders like medulloblastoma and Dandy-Walker malformation (DWM). The review consolidates findings from studies on human cerebellar development, primarily focusing on neurogenesis, the role of genetic pathways in EGL regulation, and its involvement in congenital disorders. In total 42 articles were comprehensively reviewed and the research gaps in current research on human foetal cerebellum development was highlighted. The key findings from various sections of the review are summarized as follows. In terms of gestational development, the timeline for the appearance and regression of the EGL in humans remains imprecise. Regarding morphometry, the EGL thickness shows a marked increase between 16 and 28 gestational weeks, reaching an average peak of approximately 50.05 μm around 24th to 28th weeks, and then declines during the late third trimester. In the context of gene expression, SHH signalling plays a critical role in driving the proliferation of GCPs within the EGL. When considering congenital disorders, disruptions in EGL development are associated with conditions such as medulloblastomas, DWM, and pilocytic astrocytoma. The review highlights major research gaps and underscores the need for further human-specific studies to enhance understanding and guide therapies for cerebellar disorders.