Institute of Stem Cell Research
AG 1: Neural Stem Cells
Our research aims to elucidate the key mechanisms specifying neural stem cells and their differentiated progeny. In contrast to other organs such as skin or blood where many cells continue to divide, most cells in the adult nervous system are permanently postmitotic, such as the neurons and the oligodendrocytes, and are not turned over nor regenerated once they die. Thus, the most of the neurons have to function throughout the life-time of the organism. The key issue is therefore to instruct the one cell type that is not permanently postmitotic and can still divide throughout adulthood, the astrocytes, towards (re)generation of neurons. Our work has shown that during development the astroglial-like radial glia generate the majority of neurons and oligodendrocytes (Malatesta et al., 2000; 2003), but these cells loose this potential in most brain regions at later stages. Only two small regions of the adult mammalian brain, including humans, retain astrocytes with neural stem cell properties, namely self renewal and multipotency.
Our research focuses on the telencephalon, the region that is most evolved in the human brain. The dorsal telencephalon forms the cerebral cortex, the dominant structure for information processing in humans, and the ventral telencephalon generates the basal ganglia, a centre for motor and mood control in humans. These regions are therapeutically relevant since they are affected e.g. in stroke, Alzheimer, Huntington,Schizophrenia or Parkinson patients.Their different functions are based on the presence of different neuronal subtypes that are mainly generated during development. The cerebral cortex contains predominantly glutamatergic neurons, while the basal ganglia consist mostly of GABAergic neurons (see figure below). Therefore these two regions serve as an ideal mod el system to examine the specification of neuronal subtypes. It is a general feature of the nervous system that regional specification and cell fate specification are inseparably linked (Götz et al., 1998; Götz, 2003). For the aim of neuronal reconstitution it is therefore essential to examine and to understand the mechanisms responsible for the specification of the different neuronal subtypes, since the correct type of neuron has to be regenerated.
Our key questions are:
- What are the intrinsic determinants of neurogenesis and how can they be activated
again in the adult brain to reconstitue neurons in adult brains? - What are the intrinsic and extrinsic differences between astrocytes endowed with stem cell properties and the majority of astrocytes in the remainder of the brain?
- Why do most astrocytes loose their neurogenic potential?
- What are the key mechanisms specifying neuronal subtypes?
We tackle these questions at three levels:
1) During development, the time when most neurons are generated we:
- Examine the neurogenic role of radial glial cells (see Malatesta et al. 2000, 2003, Haubst et al. 2006, Holm et al. 2007)
- Search for differential expression of FACSorted precursors followed by functional analysis (Pinto et al. 2008)
- Analyse the mode of cell division (asymmetric vs symmetric cell division) and its consequences for progenitor generation and neural stem cell self renewal (see Cappello et al. 2006, Costa et al. 2008)
- Regionalisation and patterning of the embryonic and adult brain (see von Frowein et al. 2006)
References: (Götz et al. 1998; Götz and Huttner 2005, Heins et al. 2002, Malatesta et al. 2003, Stoykova et al. 2003, Hartfuss et al. 2003, Haubst et al. 2004, Cappello et al. 2006; Haubst et al. 2006, Stricker et al. 2006, von Frowein et al. 2006, Holm et al. 2007, Costa et al. 2007, 2008, Nikoletopoulou et al. 2007)
2) At early postnatal stages when neurogenesis comes to an end and gliogenesis peaks in the mammalian forebrain:
- Screening and functional analysis of molecular factors mediating the end of neurogenesis (Pinto et al. 2008)
- Comparison to other vertebrates that have onhoing neurogenesis into adulthood (collaboration with the group of L. Bally-Cuif; see Adolf et al. 2006)
References: (Hack et al. 2004, Bibel et al. 2004, Götz and Barde 2005, Adolf et al. 2006, Berninger et al. 2007).
3) In the adult brain, where neurogenesis is restricted to two specific regions, the subependymal zone of the lateral ventricle and the dentate gyrus of the hippocampus, we
- Examine the molecular factors and the mechanisms that mediate adult neurogenesis in restricted regions (see Hack et al. 2005, Colak et al. 2008, Brill et al. 2008)
- Aim to reinitiate these mechanisms in other non-neurogenic regions of the forebrain (Buffo et al. 2008)
- Study the mechanisms and screen for molecular factors inhibiting regenerative neurogenesis after lesion in the adult mammalian brain (See Buffo et al. 2005, Colak et al. 2008)
- Aim to reinitiate these mechanisms promoting neurogenesis in the lesioned brain (see Buffo et al. 2005, 2008)
- Create tools to target specifically adult neural stem cells and glial cells in the injured brain (see Mori et al. 2006, Ninkovic et al. 2007)
References: (Mori et al 2005, Götz 2003, Götz 2001, Heins et al 2002, Hack et al. 2004, 2005, Buffo et al. 2005, Mori et al. 2006, Ninkovic et al. 2007, Colak et al. 2008, Brill et al. 2008)
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