Cerebellum and neurodevelopmental disorders: RORα is a unifying force

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Cerebellar development errors are increasingly recognized as risk factors for neurodevelopmental disorders (NDDs) like ADHD, ASD, and schizophrenia.
• Evidence links cerebellar abnormalities and genetic mutations affecting Purkinje cells to motor, learning, and social deficits common in NDDs.
• Systemic abnormalities in NDDs, such as inflammation and circadian rhythm disruption, are not fully explained by cerebellar lesions alone.

Purpose of the Study:

• To investigate the role of the transcription factor Retinoid-related Orphan Receptor alpha (RORα) in cerebellar development and its potential link to NDDs.
• To explore how RORα deficiency may cause both cerebellar and systemic abnormalities observed in NDDs.
• To propose RORα as a unifying factor connecting cerebellar dysfunction and systemic issues in NDDs like ASD and schizophrenia.

Main Methods:

• Review and synthesis of phenotypic, circuit, and structural evidence.
• Analysis of RORα's role in cerebellar development.
• Examination of RORα's extra-cerebral actions and regulation of systemic processes.

Main Results:

• RORα plays a crucial role in cerebellar development; its deficiency can lead to cerebellar abnormalities.
• RORα deficiency is associated with NDD symptoms and systemic abnormalities, including inflammation and circadian rhythm disruption.
• RORα influences extra-cerebral systems, potentially explaining the systemic components of NDDs.

Conclusions:

• RORα deficiency is a potential driving force for NDDs, causing cerebellar developmental defects and affecting downstream targets.
• RORα's regulation of extracerebral systems, including inflammation, circadian rhythms, and sexual dimorphism, contributes to the systemic manifestations of NDDs.
• RORα acts as a critical link between cerebellar and systemic abnormalities in neurodevelopmental disorders.