Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning

Abstract

Coffin-Lowry syndrome (CLS) is characterized by cognitive impairment, characteristic facial and digital findings and skeletal anomalies. The gene implicated in CLS encodes RSK2, a serine/threonine kinase acting in the Ras/MAPK signalling pathway. In humans, RSK2 belongs to a family of four highly homologous proteins (RSK1-RSK4), encoded by distinct genes. RSK2 mutations in CLS patients are extremely heterogeneous. No consistent relationship between specific mutations and the severity of the disease or the expression of uncommon features has been established. Together, the data suggest an influence of environmental and/or other genetic components on the presentation of the disease. Obvious modifying genes include those encoding other RSK family members. In this study we have determined the expression of RSK1, 2 and 3 genes in various human tissues, during mouse embryogenesis and in mouse brain. The three RSK mRNAs were expressed in all human tissues and brain regions tested, supporting functional redundancy. However, tissue specific variations in levels suggest that they may also serve specific roles. The mouse Rsk3 gene was prominently expressed in the developing neural and sensory tissues, whereas Rsk1 gene expression was the strongest in various other tissues with high proliferative activity, suggesting distinct roles during development. In adult mouse brain, the highest levels of Rsk2 expression were observed in regions with high synaptic activity, including the neocortex, the hippocampus and Purkinje cells. These structures are essential components in cognitive function and learning. Based on the expression levels, our results suggest that in these areas, the Rsk1 and Rsk3 genes may not be able to fully compensate for a lack of Rsk2 function.

ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

“…Northern analysis of rsk1 expression showed that this isoform is present in most tissues but is expressed at higher levels in the kidney, lung, and pancreas (243). Analysis of rsk2 mRNA revealed that the alternative use of two different polyadenylation sites gave rise to two transcripts of 3.5 and 8.5 kb (243).…”

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

“…Brain sections (20 mm) were analyzed for injection accuracy into the habenula using fluorescent microscopy or processed for in situ hybridization using digoxigenin-labeled RNA probes, as previously described (Chotteau-Lelievre et al, 2006), with a 276-bp Rsk2 probe (Zeniou et al, 2002) and a 608-bp Oprm1 probe (accession number: NM_001039652; bp 654-1262).…”

“…RSK2 is one of the most abundant RSK forms in the brain and is expressed at the level of forebrain regions, including cortex and hippocampus, where it is best described (Zeniou et al, 2002). We also recently found prominent expression of RSK2 at the level of the habenular complex , a brain area that modulates many neural processes and is the subject of increasing attention (Lecourtier and Kelly, 2007;Hikosaka, 2010).…”

Coffin–Lowry syndrome

“…In human and mouse embryonic brain, as well as in adult mouse brain, the highest levels of RSK2 expression are observed in regions with high synaptic activity, including the neocortex, the hippocampus, and Purkinje cells, which are essential components in cognitive function and learning. 22 RSK proteins are composed of two functional kinase catalytic domains: the N-terminal kinase domain belongs to the AGC kinase family and the C-terminal kinase domain belongs to the CamK family. The two kinase domains are connected by a 100-amino-acid linker region containing a PDK docking site.…”