Development is an intricate and timely-orchestrated process. The human brain, a marvel of evolution, consists of infinite connections and finely tuned processes that allow us to perform complex tasks, from thinking and reasoning to motor coordination. The cerebellum is the pivotal region in the brain involved in multiple functions. Traditionally known for its role in motor control, recent research has expanded our understanding of the cerebellum says Jackson James, Scientist, Rajiv Gandhi Center for Biotechnology (BRIC-RGCB), Thiruvananthapuram. James is the author of the recently published article in iScience highlighting the key role of Tlx3 in cerebellum development. His research suggests that its dysfunction could also contribute to autism-like disorders.

Tlx3 (T cell leukaemia homeobox 3) is a transcription factor. Simply put, transcription factors control the activation and deactivation of the genes at the right time point. Historically, the importance of Tlx3 has already been studied. Kathleen J Millen, Professor at Seattle Children’s Research Hospital, Seattle, a leading expert in cerebellum development highlights that the complete absence of Tlx3 leads to fetal death from respiratory failure.

James and his team, developed a mouse construct using genetic techniques with Tlx3 deletion only in the cerebellum region of the brain. They now show it is essential for the maintenance of the cerebellar granule neurons (CGN), a major cell type of the cerebellum. CGNs are crucial for the cerebellum’s proper functioning. James further adds,

This process is tightly regulated involving multiple partners and alterations could potentially induce developmental disorders.

During the development process of the cerebellum, James and others show that Tlx3 plays a role in maintaining a proper balance between the proliferation of CGN progenitors and their maturation into neurons. They observed that the deletion of Tlx3 specifically during the early development of the mice brain, reduced the number of CGN progenitor cells in mice leading to disruptions in the cerebellar structure. 

Interestingly, the dysfunction of Tlx3 not only impairs the cerebellum’s structure but also affects its functionality. The cerebellum is important for motor coordination and some aspects of learning and memory. The authors pointed out that the deletion of Tlx3 could lead to neurodevelopmental disorders like autism spectrum disorder (ASD). A condition often characterised by difficulties in social interaction and impaired motor coordination.

ASD is one of the growing health concerns in the field of Paediatrics. According to the 2021 census conducted by the India Autism Center, 1 in 68 children in India showcase symptoms like ASD. Although the causes of autism are not fully understood, it is believed to arise from a combination of genetic and environmental factors that impact brain development. 

Over the years, research has identified the cerebral cortex and cerebellum to play a crucial role in autism. This new study from James and the team implicates Tlx3 as one of the many potential genetic factors in this process. They especially suggest motor coordination and social behaviour difficulties observed in individuals with ASD could be linked to Tlx3-mediated cerebellar dysfunction. Millen reinforces this link between abnormal cerebellar development due to the loss of Tlx3 and its association with ASD as an intriguing and important finding.

Moreover, this research underscores the complexity of neurodevelopmental disorders. The intricacy and timely programmed process are controlled by multiple genetic partners with the new research identifying the importance of Tlx3. Millen further adds, 

With increasing evidence highlighting the role of cerebellar dysfunction in ASD, this study further reinforces the significance of cerebellar involvement in these conditions.

This research underscores the importance of understanding the molecular mechanisms behind brain development, as these insights can guide future research into potential therapeutic strategies for treating neurodevelopmental disorders. Having said that, Millen cautions to be aware before drawing direct connections between Tlx3 gene, function in mice and human neurodevelopmental disorders. She adds that further research is needed to determine whether Tlx3 is expressed in the developing human brain, particularly in the cerebellum, in patterns similar to those observed in mice.