c-Ski in health and disease

c-Ski is an evolutionary conserved protein that is involved in diverse cellular processes such as proliferation, differentiation, transformation, and tumor progression. A large range of cellular partners of c-Ski, including transcription factors, chromatin-remodeling molecules, tumor suppressors, and nuclear hormone receptors, has been identified. Moreover, numerous mechanisms have been described by which c-Ski regulates essential signaling pathways, e.g., the TGFβ pathway. In this review, we summarize the diverse roles attributed to c-Ski during normal development and in cancer progression and discuss future strategies to unravel further the complex nature of c-Ski actions in a context-dependent manne

Expression and localization of Ski determine cell type–specific TGFβ signaling effects on the cell cycle

Transforming growth factor β (TGFβ) promotes epithelial cell differentiation but induces Schwann cell proliferation. We show that the protooncogene Ski (Sloan-Kettering viral oncogene homologue) is an important regulator of these effects. TGFβ down-regulates Ski in epithelial cells but not in Schwann cells. In Schwann cells but not in epithelial cells, retinoblastoma protein (Rb) is up-regulated by TGFβ. Additionally, both Ski and Rb move to the cytoplasm, where they partially colocalize. In vivo, Ski and phospho-Rb (pRb) appear to interact in the Schwann cell cytoplasm of developing sciatic nerves. Ski overexpression induces Rb hyperphosphorylation, proliferation, and colocalization of both proteins in Schwann cell and epithelial cell cytoplasms independently of TGFβ treatment. Conversely, Ski knockdown in Schwann cells blocks TGFβ-induced proliferation and pRb cytoplasmic relocalization. Our findings reveal a critical function of fine-tuned Ski levels in the control of TGFβ effects on the cell cycle and suggest that at least a part of Ski regulatory effects on TGFβ-induced proliferation of Schwann cells is caused by its concerted action with Rb

An animal model for Charcot-Marie-Tooth disease type 4B1

Charcot-Marie-Tooth disease (CMT) comprises a family of clinically and genetically very heterogeneous hereditary peripheral neuropathies and is one of the most common inherited neurological disorders. We have generated a mouse model for CMT type 4B1 using embryonic stem cell technology. To this end, we introduced a stop codon into the Mtmr2 locus within exon 9, at the position encoding amino acid 276 of the MTMR2 protein (E276X). Concomitantly, we have deleted the chromosomal region immediately downstream of the stop codon up to within exon 13. The resulting allele closely mimics the mutation found in a Saudi Arabian CMT4B1 patient. Animals homozygous for the mutation showed various degrees of complex myelin infoldings and outfoldings exclusively in peripheral nerves, in agreement with CMT4B1 genetics and pathology. Mainly, paranodal regions of the myelin sheath were affected, with a high degree of quantitative and qualitative variability between individuals. This pathology was progressive with age, and axonal damage was occasionally observed. Distal nerve regions were more affected than proximal parts, in line with the distribution in CMT. However, we found no significant electrophysiological changes, even in aged (16-month-old) mice, suggesting that myelin infoldings and outfoldings per se are not invariably associated with detectable electrophysiological abnormalities. Our animal model provides a basis for future detailed molecular and cellular studies on the underlying disease mechanisms in CMT4B1. Such an analysis will reveal how the disease develops, in particular, the enigmatic myelin infoldings and outfoldings as well as axonal damage, and provide mechanistic insights that may aid in the development of potential therapeutic approache

Temporal and sequential transcriptional dynamics define lineage shifts in corticogenesis

The cerebral cortex contains billions of neurons, and their disorganization or misspecification leads to neurodevelopmental disorders. Understanding how the plethora of projection neuron subtypes are generated by cortical neural stem cells (NSCs) is a major challenge. Here, we focused on elucidating the transcriptional landscape of murine embryonic NSCs, basal progenitors (BPs), and newborn neurons (NBNs) throughout cortical development. We uncover dynamic shifts in transcriptional space over time and heterogeneity within each progenitor population. We identified signature hallmarks of NSC, BP, and NBN clusters and predict active transcriptional nodes and networks that contribute to neural fate specification. We find that the expression of receptors, ligands, and downstream pathway components is highly dynamic over time and throughout the lineage implying differential responsiveness to signals. Thus, we provide an expansive compendium of gene expression during cortical development that will be an invaluable resource for studying neural developmental processes and neurodevelopmental disorders

c-Ski in health and disease

c-Ski is an evolutionary conserved protein that is involved in diverse cellular processes such as proliferation, differentiation, transformation, and tumor progression. A large range of cellular partners of c-Ski, including transcription factors, chromatin-remodeling molecules, tumor suppressors, and nuclear hormone receptors, has been identified. Moreover, numerous mechanisms have been described by which c-Ski regulates essential signaling pathways, e.g., the TGFβ pathway. In this review, we summarize the diverse roles attributed to c-Ski during normal development and in cancer progression and discuss future strategies to unravel further the complex nature of c-Ski actions in a context-dependent manner

Cyclins, Cyclin-Dependent Kinases, and Cyclin-Dependent Kinase Inhibitors in the Mouse Nervous System

Development and normal physiology of the nervous system require proliferation and differentiation of stem and progenitor cells in a strictly controlled manner. The number of cells generated depends on the type of cell division, the cell cycle length, and the fraction of cells that exit the cell cycle to become quiescent or differentiate. The underlying processes are tightly controlled and modulated by cyclin-dependent kinases (Cdks) and their interactions with cyclins and Cdk inhibitors (CKIs). Studies performed in the nervous system with mouse models lacking individual Cdks, cyclins, and CKIs, or combinations thereof, have shown that many of these molecules control proliferation rates in a cell-type specific and time-dependent manner. In this review, we will provide an update on the in vivo studies on cyclins, Cdks, and CKIs in neuronal and glial tissue. The goal is to highlight their impact on proliferation processes during the development of the peripheral and central nervous system, including and comparing normal and pathological conditions in the adult

Modulating epigenetic mechanisms: the diverse functions of Ski during cortical development

In the developing forebrain, neural stem and progenitor cells generate a large variety of neurons with specific functions in the mature cortex. A central issue is to understand the roles of transcriptional networks and regulatory pathways that control these complex developmental processes. The proto-oncogene Ski is a transcriptional regulator linked to the human 1p36 deletion syndrome, which involves a set of phenotypes including nervous system defects. Ski shows a dynamic expression pattern during cortical development and, accordingly, the phenotype of Ski-deficient cortices is complex, involving altered cell cycle characteristics of neural progenitors, disturbed timing of neurogenesis and mis-specification of projection neurons. Ski is likely to play a role in various pathways by virtue of its ability to interact with a range of signaling molecules, thereby modulating transcriptional activity of corresponding target genes. Ski regulates proliferation and differentiation of various cell types, and more recent data from my laboratory demonstrates that Ski is also involved in the specification of cortical projection neurons. This Point-of-View elucidates the role of Ski as an essential linker between sequence-specific transcription factors and non-DNA binding cofactors with chromatin modifying activities. In particular, it puts forward the hypothesis that the diverse functions of Ski as a co-repressor might be related to its association with distinct HDAC-complexes

ErbB2 signaling in Schwann cells is mostly dispensable for maintenance of myelinated peripheral nerves and proliferation of adult Schwann cells after injury

Neuregulin/erbB signaling is critically required for survival and proliferation of Schwann cells as well as for establishing correct myelin thickness of peripheral nerves during development. In this study, we investigated whether erbB2 signaling in Schwann cells is also essential for the maintenance of myelinated peripheral nerves and for Schwann cell proliferation and survival after nerve injury. To this end, we used inducible Cre-loxP technology using a PLP-CreERT2 allele to ablate erbB2 in adult Schwann cells. ErbB2 expression was markedly reduced after induction of erbB2 gene disruption with no apparent effect on the maintenance of already established myelinated peripheral nerves. In contrast to development, Schwann cell proliferation and survival were not impaired in mutant animals after nerve injury, despite reduced levels of MAPK-P (phosphorylated mitogen-activated protein kinase) and cyclin D1. ErbB1 and erbB4 do not compensate for the loss of erbB2. We conclude that adult Schwann cells do not require major neuregulin signaling through erbB2 for proliferation and survival after nerve injury, in contrast to development and in cell culture

Mice lacking protease nexin-1 show delayed structural and functional recovery after sciatic nerve crush

Multiple molecular mechanisms influence nerve regeneration. Because serine proteases were shown to affect peripheral nerve regeneration, we performed nerve crush experiments to study synapse reinnervation in adult mice lacking the serpin protease nexin-1 (PN-1). PN-1 is a potent endogenous inhibitor of thrombin, trypsin, tissue plasminogen activators (tPAs), and urokinase plasminogen activators. Compared with the wild type, a significant delay in synapse reinnervation was detected in PN-1 knock-out (KO) animals, which was associated with both reduced proliferation and increased apoptosis of Schwann cells. Various factors known to affect Schwann cells were also altered. Fibrin deposits, tPA activity, mature BDNF, and the low-affinity p75 neurotrophin receptor were increased in injured sciatic nerves of mutant mice. To test whether the absence of PN-1 in Schwann cells or in the axon caused delay in reinnervation, PN-1 was overexpressed exclusively in the nerves of PN-1 KO mice. Neuronal PN-1 expression did not rescue the delayed reinnervation. The results suggest that Schwann cell-derived PN-1 is crucial for proper reinnervation through its contribution to the autocrine control of proliferation and survival. Thus, the precise balance between distinct proteases and serpins such as PN-1 can modulate the overall impact on the kinetics of recovery