Stem Cell Neurogenesis and Parkinson’s disease
Harnessing the incredible regenerative power of stem cells is central to many scientists’ and medical practitioners’ visions of medicine in the future. Beyond the controversy of embryo-derived stem cells lies the middle-distance goal of using normal adult cells and inducing them to become pluripotent – the special ability of stem cells that allows them to become any human cell type. While the way is littered with obstacles, this is a milestone within reach: plentiful viable stem cells are closer than we think. But what comes next? Beyond iPS (induced Pluripotent Stem) cells on the horizon of discovery lies another milestone: the point at which we can direct the iPS cell to become the cell type required for a given therapy.
Understanding the biological mechanisms that point the way to this level of cell determinacy is like holding the blank square in Scrabble: it can be any letter we choose. Currently however, we don’t know all of the rules of the game.
Researchers in the CSC Stem Cell Neurogenesis group headed by Meng Li are attempting to illuminate these biological rules. In particular, they are investigating how midbrain dopamine neurons – the brain cells involved in pleasure and reward – are formed from stem cells. These cells become damaged in patients with Parkinson’s disease, so a future therapy making their regeneration a possibility would be an extremely valuable one. So what biological switches and mechanisms determine this particular fate for the cell rather than it becoming another type of brain cell?
Meng’s team looked at how certain transcription factors – protein molecules that help to determine cell type by switching individual genes on or off – come into play to make midbrain dopamine neurons. They focused on a particular class of transcription factors that normally play a role in the development of the sexual organs, called Dmrt. One of which, Dmrt4, has being previously found to be important in the development of the sense of smell in some species. In experiments on mouse embryonic stem cells and chicken embryos, the researchers found that Dmrt5 was vital for the development of midbrain neurons.
Cells producing Dmrt5 become midbrain dopamine neurons while cells lacking the ability to make Dmrt5 became GABAergic neurons; indicating that Dmrt5 actively blocks a potential fate – the possibility of becoming a GABAergic neuron – in addition to promoting the dopamine neuron fate.
But do we know anything about how Dmrt5 is doing this?
Meng explains: “Dmrt5 imposes a pre-dopaminergic molecular codes on neural stem cells while simultaneously prevent them from acquiring the potential to make other types of nerve cells. Our ongoing works aims to reveal the detailed molecular mechanisms of how Dmrt5 regulates these developmental decisions of stem cells.”
Understanding the biological rules that come into play to direct a particular fate for a cell is a key step towards being able to make whatever cell type we choose. Not only could this research one day lead to therapies for Parkinson’s disease and other neurodegenerative conditions, it provides vital clues to the development of function of one of nature’s most complex puzzles: the brain.
SJ
This work was published in PNAS
Reference: Gennet N, Gale E, Nan X, Takacs K, Oberwallner B and Li M (2011). Dmrt5 promotes midbrain dopaminergic identity in pluripotent stem cells by enforcing a ventral medial progenitor fate. PNAS 108, 9131-9136.
