Selective alteration of adult hippocampal neurogenesis and impaired spatial pattern separation performance in the RSK2-deficient mouse model of Coffin-Lowry syndrome.

Adult neurogenesis is involved in certain hippocampus-dependent cognitive functions and is linked to psychiatric diseases including intellectual disabilities. The Coffin-Lowry syndrome (CLS) is a developmental disorder caused by mutations in the Rsk2 gene and characterized by intellectual disabilities associated with growth retardation. How RSK2-deficiency leads to cognitive dysfunctions in CLS is however poorly understood.

PLD1 participates in BDNF-induced signalling in cortical neurons.

The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1(-/-) neurons.

The PDK1-Rsk Signaling Pathway Controls Langerhans Cell Proliferation and Patterning.

Langerhans cells (LC), the dendritic cells of the epidermis, are distributed in a distinctive regularly spaced array. In the mouse, the LC array is established in the first few days of life from proliferating local precursors, but the regulating signaling pathways are not fully understood. We found that mice lacking the kinase phosphoinositide-dependent kinase 1 selectively lack LC.

Structural and functional basis for p38-MK2-activated Rsk signaling in toll-like receptor-stimulated dendritic cells.

Rsk kinases play important roles in several cellular processes such as proliferation, metabolism, and migration. Until recently, Rsk activation was thought to be exclusively initiated by Erk1/2, but in dendritic cells (DC) Rsk is also activated by p38 mitogen-activated protein (MAP) kinase via its downstream substrates, MK2/3. How and why this noncanonical configuration of the MAP kinase pathway is adopted by these key immune cells are not known.

RSK2 is a modulator of craniofacial development.

Background: The RSK2 gene is responsible for Coffin-Lowry syndrome, an X-linked dominant genetic disorder causing mental retardation, skeletal growth delays, with craniofacial and digital abnormalities typically associated with this syndrome. Craniofacial and dental anomalies encountered in this rare disease have been poorly characterized.

Methodology/principal Findings: We examined, using X-Ray microtomographic analysis, the variable craniofacial dysmorphism and dental anomalies present in Rsk2 knockout mice, a model of Coffin-Lowry syndrome, as well as in triple Rsk1,2,3 knockout mutants.

The Coffin-Lowry syndrome-associated protein RSK2 regulates neurite outgrowth through phosphorylation of phospholipase D1 (PLD1) and synthesis of phosphatidic acid.

More than 80 human X-linked genes have been associated with mental retardation and deficits in learning and memory. However, most of the identified mutations induce limited morphological alterations in brain organization and the molecular bases underlying neuronal clinical features remain elusive. We show here that neurons cultured from mice lacking ribosomal S6 kinase 2 (Rsk2), a model for the Coffin-Lowry syndrome (CLS), exhibit a significant delay in growth in a similar way to that shown by neurons cultured from phospholipase D1 (Pld1) knock-out mice.

Defective synaptic transmission and structure in the dentate gyrus and selective fear memory impairment in the Rsk2 mutant mouse model of Coffin-Lowry syndrome.

The Coffin-Lowry syndrome (CLS) is a syndromic form of intellectual disability caused by loss-of-function of the RSK2 serine/threonine kinase encoded by the rsk2 gene. Rsk2 knockout mice, a murine model of CLS, exhibit spatial learning and memory impairments, yet the underlying neural mechanisms are unknown. In the current study, we examined the performance of Rsk2 knockout mice in cued, trace and contextual fear memory paradigms and identified selective deficits in the consolidation and reconsolidation of hippocampal-dependent fear memories as task difficulty and hippocampal demand increase.

Rsk2 Knockdown in PC12 Cells Results in Sp1 Dependent Increased Expression of the Gria2 Gene, Encoding the AMPA Receptor Subunit GluR2.

The RSK2 protein is a member of the RSK serine-threonine protein kinase family and is encoded by the X-linked rps6ka3 gene in human. Highly heterogeneous loss-of-function mutations affecting this gene are responsible for a severe syndromic form of cognitive impairment, Coffin-Lowry syndrome. RSK2, which is highly conserved in mammals, acts at the distal end of the Ras-ERK signaling pathway and is activated in response to growth factors and neurotransmitters.

Identification of the first deep intronic mutation in the RPS6KA3 gene in a patient with a severe form of Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS) is an X-linked disorder characterized by growth and psychomotor retardation, hypotonia and progressive skeletal changes. RPS6KA3 is the only gene known to be associated with CLS, and over 150 distinct inactivating mutations in this gene have so far been reported in CLS patients. However, no defect is found in about half of the CLS compatible patients by exon sequencing.

Anchored p90 ribosomal S6 kinase 3 is required for cardiac myocyte hypertrophy.

Rationale: Cardiac myocyte hypertrophy is the main compensatory response to chronic stress on the heart. p90 ribosomal S6 kinase (RSK) family members are effectors for extracellular signal-regulated kinases that induce myocyte growth. Although increased RSK activity has been observed in stressed myocytes, the functions of individual RSK family members have remained poorly defined, despite being potential therapeutic targets for cardiac disease.

Stimulus-induced drop episodes in Coffin-Lowry syndrome.

The Coffin-Lowry syndrome (CLS) is a rare but well-defined X-linked semidominant syndrome characterized by psychomotor and growth retardation, and progressive skeletal changes. CLS is caused by loss of function mutations in the Rps6ka3 gene encoding the ribosomal S6 kinase 2 (RSK2) protein. A distinctive paroxysmal disorder has been described in some CLS patients, characterized by episodes of sudden falling, without apparent alteration of consciousness, usually induced by unexpected tactile or auditory stimuli.

RSK2 signaling in medial habenula contributes to acute morphine analgesia.

It has been established that mu opioid receptors activate the ERK1/2 signaling cascade both in vitro and in vivo. The Ser/Thr kinase RSK2 is a direct downstream effector of ERK1/2 and has a role in cellular signaling, cell survival growth, and differentiation; however, its role in biological processes in vivo is less well known. Here we determined whether RSK2 contributes to mu-mediated signaling in vivo.

RSK2 signaling in brain habenula contributes to place aversion learning.

RSK2 is a Ser/Thr kinase acting in the Ras/MAPK pathway. Rsk2 gene deficiency leads to the Coffin-Lowry Syndrome, notably characterized by cognitive deficits. We found that mrsk2 knockout mice are unable to associate an aversive stimulus with context in a lithium-induced conditioned place aversion task requiring both high-order cognition and emotional processing.

Altered ERK/MAPK signaling in the hippocampus of the mrsk2_KO mouse model of Coffin-Lowry syndrome.

Coffin-Lowry syndrome is a syndromic form of mental retardation caused by mutations of the Rps6ka3 gene encoding ribosomal s6 kinase (RSK)2. RSK2 belongs to a family containing four members in mammals: RSK1-4. RSKs are serine/threonine kinases and cytosolic substrates of extracellular signal-regulated kinase (ERK) in the Ras/MAPK signaling pathway.

Transcriptome profile reveals AMPA receptor dysfunction in the hippocampus of the Rsk2-knockout mice, an animal model of Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS) is a syndromic form of mental retardation caused by loss of function mutations in the X-linked RPS6KA3 gene, which encodes RSK2, a serine/threonine kinase acting in the MAPK/ERK pathway. The mouse invalidated for the Rps6ka3 (Rsk2-KO) gene displays learning and long-term spatial memory deficits. In the current study, we compared hippocampal gene expression profiles from Rsk2-KO and normal littermate mice to identify changes in molecular pathways.

Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation, which is characterized in male patients by psychomotor and growth retardation and various skeletal anomalies. Typical facial changes and specific clinical and radiological signs in the hand are useful aids in the diagnosis. CLS is caused by mutations in the RPS6KA3 gene located at Xp22.

P90 Ribosomal s6 kinase 2 negatively regulates axon growth in motoneurons.

Mutations in Ribosomal s6 kinase 2 (Rsk2) are associated with severe neuronal dysfunction in Coffin-Lowry syndrome (CLS) patients, flies and mice. So far, the mechanisms of how Rsk2 regulates development, maintenance and activity of neurons are not understood. We have investigated the consequences of Rsk2 deficiency in mouse spinal motoneurons.

Fibroblast growth factor receptor 3 associates with and tyrosine phosphorylates p90 RSK2, leading to RSK2 activation that mediates hematopoietic transformation.

Dysregulation of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) plays a pathogenic role in a number of human hematopoietic malignancies and solid tumors. These include t(4;14) multiple myeloma associated with ectopic expression of FGFR3 and t(4;12)(p16;p13) acute myeloid leukemia associated with expression of a constitutively activated fusion tyrosine kinase, TEL-FGFR3. We recently reported that FGFR3 directly tyrosine phosphorylates RSK2 at Y529, which consequently regulates RSK2 activation.

Dopaminergic system dysregulation in the mrsk2_KO mouse, an animal model of the Coffin-Lowry syndrome.

The Coffin-Lowry syndrome, a rare syndromic form of X-linked mental retardation, is caused by loss-of-function mutations in the hRSK2 (RPS6KA3) gene. To further investigate RSK2 (90-kDa ribosomal S6 kinase) implication in cognitive processes, a mrsk2_KO mouse has previously been generated as an animal model of Coffin-Lowry syndrome. The aim of the present study was to identify possible neurochemical dysregulation associated with the behavioral and morphological abnormalities exhibited by mrsk2_KO mice.

The Coffin-Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1.

Exocytosis of neurotransmitters and hormones occurs through the fusion of secretory vesicles with the plasma membrane. This highly regulated process involves key proteins, such as SNAREs, and specific lipids at the site of membrane fusion. Phospholipase D (PLD) has recently emerged as a promoter of membrane fusion in various exocytotic events potentially by providing fusogenic cone-shaped phosphatidic acid.

Inactivation of the CDKL3 gene at 5q31.1 by a balanced t(X;5) translocation associated with nonspecific mild mental retardation.

We have investigated the breakpoints of a balanced reciprocal translocation between chromosomes X and 5, [46,X,t(X;5)(p11.1;q31.1)], in a woman with mild mental retardation (MR).

The first large duplication of the RSK2 gene identified in a Coffin-Lowry syndrome patient.

Heterogeneous mutations in the X-linked gene RPS6KA3, encoding the protein kinase RSK2, are responsible for Coffin-Lowry Syndrome. Here we have further studied a male patient with a highly suggestive clinical diagnosis of CLS but in whom no mutation was found by exon sequencing. Western blot analysis revealed a protein much larger than the normal expected size.

Genetic background of HSH in three Polish families and a patient with an X;9 translocation.

Hypomagnesemia with secondary hypocalcemia (HSH) is a rare inherited disease, characterised by neurological symptoms, such as tetany, muscle spasms and seizures, due to hypocalcemia. It has been suggested that HSH is genetically heterogeneous, but only one causative gene, TRPM6, on chromosome 9 has so far been isolated. We have now studied the genetic background of HSH in four Polish patients belonging to three families, and a HSH patient carrying an apparently balanced X;9 translocation.

Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation.

The extensive heterogeneity underlying the genetic component of mental retardation (MR) is the main cause for our limited understanding of the aetiology of this highly prevalent condition. Hence we set out to identify genes involved in MR. We investigated the breakpoints of two balanced X;autosome translocations in two unrelated female patients with mild/moderate MR and found that the Xp11.

p90Rsk is not involved in cytostatic factor arrest in mouse oocytes.

Vertebrate oocytes arrest in metaphase of the second meiotic division (MII), where they maintain a high cdc2/cyclin B activity and a stable, bipolar spindle because of cytostatic factor (CSF) activity. The Mos-MAPK pathway is essential for establishing CSF. Indeed, oocytes from the mos-/- strain do not arrest in MII and activate without fertilization, as do Xenopus laevis oocytes injected with morpholino oligonucleotides directed against Mos.