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Published on: January 12, 2015
Coffin-Lowry syndrome: a role for RSK2 in mammalian neurogenesis
Chandrasagar B Dugani1, Annie Paquin, David R Kaplan
1Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1L7.
Abstract:
Coffin-Lowry Syndrome (CLS) is an X-linked genetic disorder associated with cognitive and behavioural impairments. CLS patients present with loss-of-function mutations in the RPS6KA3 gene encoding the mitogen-activated protein kinase (MAPK)-activated kinase p90 ribosomal S6 kinase 2 (Rsk2). Although Rsk2 is expressed in the embryonic brain, its function remains largely uncharacterized. To this end, we isolated murine cortical precursors at embryonic day 12 (E12), a timepoint when neuronal differentiation is initiated, and knocked-down Rsk2 expression levels using shRNA. We performed similar experiments in vivo using in utero electroporations to express shRNA against Rsk2. Rsk2 knockdown resulted in a significant decrease in neurogenesis and an increase in the proportion of proliferating Pax6-positive radial precursor cells, indicating that Rsk2 is essential for cortical radial precursors to differentiate into neurons. In contrast, reducing Rsk2 levels in vitro or in vivo had no effect on the generation of astrocytes. Thus, Rsk2 loss-of-function, as seen in CLS, perturbs the differentiation of neural precursors into neurons, and maintains them instead as proliferating radial precursor cells, a defect that may underlie the cognitive dysfunction seen in CLS.
Insights
Coffin-Lowry Syndrome (CLS) is linked to RPS6KA3 gene mutations. Loss of Rsk2 protein impairs neural precursor differentiation into neurons, potentially causing cognitive deficits in CLS patients.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Coffin-Lowry Syndrome (CLS) is an X-linked disorder linked to RPS6KA3 gene mutations.
- The function of p90 ribosomal S6 kinase 2 (Rsk2) in embryonic brain development is largely unknown.
- Rsk2 is a mitogen-activated protein kinase (MAPK)-activated kinase crucial for cellular signaling.
Purpose of the Study:
- To investigate the role of Rsk2 in embryonic cortical development and neurogenesis.
- To determine if Rsk2 is essential for the differentiation of neural precursor cells into neurons.
- To understand how Rsk2 loss-of-function in CLS may contribute to cognitive impairments.
Main Methods:
- Knockdown of Rsk2 expression in murine cortical precursors using short hairpin RNA (shRNA) in vitro.
- In vivo knockdown of Rsk2 using in utero electroporation in mouse embryos.
- Analysis of neurogenesis and cell proliferation markers (Pax6) in radial precursor cells.
Main Results:
- Rsk2 knockdown significantly decreased neurogenesis in developing mouse cortices.
- Reduced Rsk2 levels led to an increased proportion of proliferating Pax6-positive radial precursor cells.
- Rsk2 loss-of-function did not affect astrocyte generation.
Conclusions:
- Rsk2 is essential for the proper differentiation of cortical radial precursor cells into neurons.
- Loss of Rsk2 function perturbs neurogenesis, maintaining precursors in a proliferative state.
- This defect in neuronal differentiation due to Rsk2 loss may underlie the cognitive dysfunction observed in Coffin-Lowry Syndrome.
