Molecular Mechanisms in Neurodevelopment and Neurodegeneration
Neural stem cells are a focus of public and scientific interest, since with the discovery of neurogenesis in the adult brain we can think of novel strategies for the treatment of neurodegenerative diseases. The characterization of neural stem cells during brain development and repair is a prerequisite for the design of therapeutic procedures. The central nervous system (CNS) develops from self-renewing, multipotent neural stem cells present in different regions of the embryonic nervous system, where they are regionally and temporally restricted. Moreover, there is increasing evidence that mechanisms of regeneration are distinct from those of development. A central and challenging issue is to identify the extrinsic and intrinsic factors, which control the balance of self-renewal, proliferation, and cell fate decisions in a context-dependent manner. With our projects, we expect to obtain considerable insights into the expression and function of candidate genes controlling proliferation and differentiation of neural stem/progenitor cells during cortical and spinal cord development and following brain injuries.
Our group is investigating the role of the transcriptional regulator Ski and specific cell cycle proteins as part of the mechanisms by which maintenance and proliferation of progenitor cells are controlled. In the peripheral nervous system (PNS), we have identified Ski as a key player in the regulation of Schwann cell proliferation and myelination (Atanasoski et al., 2004; Jacob et al., 2008). Further, we have discovered that certain signaling pathways and distinct components of the cell cycle machinery that regulate Schwann cell proliferation during development differ fundamentally from those activated following nerve injury (Atanasoski et al., 2006, 2008).
Our recent work in the CNS shows that Ski is expressed in Sox2-positive neural stem cells throughout embryonic development, and that it plays an essential role in the temporal control of progenitor cell differentiation in the dorsal forebrain (Baranek et al., submitted). Moreover, in Ski mutant mice neurons of the superficial cortical layers lose their identity and largely fail to extend across the corpus callosum (Fig. 1). They ectopically express Ctip2, a transcription factor whose expression is normally confined to subsets of deep-layer neurons. We identify the chromatin-remodeling factor Satb2 as a novel interaction partner of Ski, and show that the presence of both proteins is required for transcriptional repression of Ctip2 in callosal neurons. We propose a model in which Satb2 recruits Ski to the Ctip2 locus, and Ski in turn attracts histone deacetylases, thereby enabling the formation of a functional repressor complex (Fig. 2). Our data identify Ctip2 as the first in vivo target of Ski and suggest that Ski and Satb2 function in a common pathway that is necessary for specification of callosal projection neurons (Baranek et al., submitted). Our future studies are aimed at unraveling the mechanisms by which loss of Ski leads to cell cycle lengthening and precocious cell cycle exit of progenitor cells. Thus, we have established a cell culture system that allows us to elucidate the cellular function of Ski specifically in the neuronal lineage. Such cultures provide a good test system, in that the regulation of progenitor cell proliferation and differentiation can be manipulated by extracellular factors and by genetic means.
The overall goal of our projects is to improve our understanding of the pathways and molecules that regulate proliferation and differentiation in neural and glial progenitor cells from different regions in the CNS. Knowledge of how these cells can be maintained and induced to differentiate into distinct cell types, respectively, will have implications for future clinical applications, such as Parkinson’s disease, multiple sclerosis, or spinal cord injuries.