The RAS/MAPK pathway is a critical signaling cascade that is involved in various cellular functions including growth, differentiation, survival, and apoptosis. It plays a significant role both in the normal physiology of the brain and in the pathophysiology of cancer. The importance of the RAS/MAPK pathway in both the brain and cancer illustrates a broader principle of cellular biology: the same signaling mechanisms that are critical for normal cellular and physiological functions can, when dysregulated, contribute to disease. Therefore, the balance of signaling is crucial where too little signaling can lead to impaired development or brain function, while too much can contribute to the development and progression of cancer. Understanding the RAS/MAPK pathway is essential for developing new therapeutic strategies for neurodevelopmental disorders and cancers. The complexity of the pathway also reflects the challenges in targeting it therapeutically, as interventions must be finely tuned to correct the signaling imbalance without disrupting the normal functions of the pathway. A new study conducted by Dr. Sara Knowles, Associate Professor Jason Newbern, April Stafford, MS, Dr. Tariq Zaman, Dr. Kartik Angara, Dr. Michael Williams, and led by Professor Daniel Vogt from Arizona State University and Michigan State University investigated the impact of hyperactive RAS/MAPK signaling on the development of GABAergic cortical interneurons (CINs) and their role in the etiology of these disorders.
The researchers proposed that GABAergic dysfunction, particularly in the form of alterations in parvalbumin (PV) and somatostatin (SST) expressing CINs, may play a pivotal role in the cognitive changes associated with RAS/MAPK disorders. They examined how hyperactivation of RAS/MAPK signaling in animal models affects the development of these distinct CIN types. Moreover, they focused on understanding how these different CIN types emerge from the same progenitor cells during embryonic development and whether RAS/MAPK signaling plays a role in this process.
The research team found that hyperactive RAS/MAPK signaling leads to a bias towards SST-expressing CINs at the expense of PV-expressing CINs. This observation highlights the potential role of RAS/MAPK signaling in shaping the molecular properties of CINs during development. The study also showed that the altered ratio of SST+ and PV+ CINs was a common feature in two distinct RAS/MAPK hyperactive mutants. The authors’ findings have important implications for understanding the shared phenotypes and potential therapeutic targets in RASopathies, a group of genetic disorders caused by mutations in RAS/MAPK pathway genes. Since common changes in CINs are induced by hyperactive RAS/MAPK signaling, this research provides valuable insights that could inform future therapeutic approaches for the broad RASopathy family.
Additionally, the authors investigated the role of key transcription factors, such as LHX6, in the development of distinct CIN populations from the medial ganglionic eminence (MGE). These experiments contributed to our understanding of how different CIN types with unique molecular, morphological, and electrophysiological properties emerge from the same progenitor cells during embryonic development. Moreover, the researchers explored the impact of hyperactive RAS/MAPK signaling on CIN electrophysiological properties, indicating a shift towards SST-like properties in mutant CINs. This finding enhances our understanding of how alterations in RAS/MAPK signaling can influence the functional properties of CINs.
Professor Daniel Vogt and colleagues also identified changes in the expression of core developmental genes involved in cell fate and function in hyperactive RAS/MAPK mutants. These alterations further elucidate the molecular mechanisms underlying the observed phenotypic changes in CINs. Furthermore, the study uncovered the role of SATB1 as a potential mediator of the elevated SST expression observed in hyperactive RAS/MAPK mutants. SATB1’s increased expression in mutant CINs during development suggests its involvement in cell fate bias towards SST-expressing CINs. These findings provide valuable insights into the regulatory mechanisms governing CIN development in the context of RAS/MAPK signaling. Additionally, the research highlights a reduction in ARX expression in both Nf1 cKO and bRafca mutants, suggesting that ARX is another factor contributing to the observed phenotypes. Understanding the role of ARX in CIN development and function can provide further insights into the mechanisms underlying RAS/MAPK-related neurodevelopmental disorders.
The study’s findings also have therapeutic implications, as pharmacological blockade of MEK signaling with selumetinib was shown in their experiments to normalize SST expression in hyperactive RAS/MAPK mutants. This suggests that targeted interventions aimed at modulating RAS/MAPK signaling may hold promise for mitigating the observed CIN phenotypes and associated cognitive symptoms in RASopathies.
In conclusion, the study by Professor Daniel Vogt and colleagues offers a comprehensive investigation into the impact of hyperactive RAS/MAPK signaling on the development and function of GABAergic CINs. Their findings provide valuable insights into the molecular mechanisms underlying RASopathies, particularly molecular and cellular candidates that may underlie cognitive symptoms, and suggest potential therapeutic strategies for addressing these conditions. This research contributes significantly to our understanding of the complex interplay between genetics, cellular signaling, and neurodevelopment.
Knowles SJ, Stafford AM, Zaman T, Angara K, Williams MR, Newbern JM, Vogt D. Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs. Development. 2023;150(10):dev201371. doi: 10.1242/dev.201371.