Forschungsgruppe Yves-Alain Barde
Stem cells and neural development in health and disease
Much of our work focuses on a small family of signaling molecules designated neurotrophins. These growth factors have been identified in the genome of long-lived species, but not in short-lived invertebrates typically used by geneticists. This is unusual and explains why forward genetics could not contribute to this field of research. Long-lived species may benefit from the multiple roles played by neurotrophins in adaptive phenomena, such as the ability of an organism to detect, store and interpret external stimuli, including those that are potentially damaging.
Neurotrophins in health and disease
The neurotrophin brain-derived neurotrophic factor (BDNF) is encoded by a gene that is positively regulated by neuronal activity. Our research concentrates on BDNF as together with its receptor, it is much more widely expressed in the central nervous system than the other genes of the family. In collaboration with the group of Michael Frotscher (then in Freiburg, Germany) we could show that BDNF is stored in pre-synaptic, large dense core vesicles. When activity is chronically increased as observed in a mouse mutant developing epileptic seizures in the adult, BDNF is expressed at much higher levels than in control animals, while its processing and sub-cellular distribution remain as in wild-type animals (see Dieni et al., 2012). Remarkably, the brain of these animals markedly increases in size, in parallel with a post-natal increase in BDNF levels. As we previously showed that conversely, the lack of BDNF leads to smaller adult brains (Rauskolb et al., 2010), we are now exploring how BDNF regulates brain growth. In a mouse model of Rett syndrome, the levels of BDNF are decreased in parallel with a reduction in brain size and we found that BDNF levels can be restored close to normal following the administration of fingolimod (Deogracias et al., 2012). This treatment also increases the size of some of the brain areas affected by the lack of the gene causing Rett syndrome, MECP2 (Deogracias et al., 2012). Fingolimod is a drug of special interest as it has been recently introduced for the treatment of multiple sclerosis. It is closely related to the endogenous lipid sphingosine and diffuses into the brain. Our work suggests that it activates receptors present on brain neurons, leading to an increase synaptic activity which in turns increases BDNF levels. We hope that beyond Rett syndrome, these results will also be useful in the context of other diseases of the nervous system that may be ameliorated by increasing BDNF levels.
Embryonic stem cells
The discovery that mouse ES cells can be used to generate essentially pure populations of neurons has greatly facilitated the understanding of genes expressed in neurons. Some of these genes have been very difficult to study in the past given the lack of relevant cell culture systems. The uniform population of Pax6-positive radial glial cells generated by our method under well-defined tissue culture conditions goes on to generate glutamatergic neurons with the functional characteristics of the brain neurons. This extraordinarily powerful system allowed us to uncover new roles for the transcription factor Pax6 (Nikoletopoulou et al., 2007), the amyloid precursor protein APP (Schrenk-Siemens et al., 2008), the neurotrophin receptors p75 (Plachta et al., 2007), TrkA and TrkC (Nikoletopoulou et al., 2010) and MeCP2. The gene most frequently mutated in Rett syndrome (Yazdani et al., 2012, see Publications for detailed accounts of these findings). This system also allowed the discovery of novel downstream targets of p75 including the endogenous lectin Galectin-1, which turned out to play an essential role in seizure-induced neuronal death in vivo (Bischoff et al., 2012).
- Fig. 1: Fluoro Jade B labels dying cells (green dots) following pilocarpine injection. Pilocarpine is a drug that induces seizure episodes and causes the death of neurons. (Note that in animals lacking the Galectin-1 gene (Lgal1 -/-), pilocarpine fails to cause cell death even though it also induces seizure like in wild-type animals. For additional details see Bischoff et al. 2012 in Publications.)
