Driving neurogenesis in the adult brain
Neural stem cells in the adult brain have the capacity to differentiate into distinct cell types, giving rise to both nerve cells and glia. A new study has identified a set of proteins that is essential for acquisition of the neuronal cell fate.
In mammals, including humans, the vast majority of neurons are generated during the embryonic and early post-natal phases of development. In adult life, neurogenesis is restricted to a few areas in the mammalian forebrain, while the remainder of the central nervous system comprises exclusively glial progenitors. Indeed the adult brain is a very giogenic environment, such that even neural stem cells that are transplanted in experimental attempts to treat neurodegenerative diseases give rise to glial cells rather than neurons. This has led researchers to focus their attention on those few brain regions where neurogenesis continues to occur in adult mammals, in order to identify the mechanisms allowing neural stem cells to successfully generate neurons in this region.
What decides whether multipotent stem cells differentiate into nerve cells or glia? “Both in the developing and in the adult brain, many transcription factors are known to play a role in neurogenesis,” says Professor Magdalena Götz, who holds the Chair of Physiological Genomics at LMU’s Institute of Physiology and is Director of the Institute of Stem Cell Research at the Helmholtz Munich. “But nothing is yet known about how these factors mediate neurogenesis at the molecular level and to which extent fate-stabilizing mechanisms may be required in the adult brain where otherwise only glial cells are generated.”
A team of researchers led by Götz has now reported the results of a study in which they have succeeded in characterizing a key mechanism in the process. They set out to discover interaction partners of the neurogenic transcription factor Pax6, which is known from the work of the Götz lab to play a prominent role in both brain development and adult neurogenesis. “We have shown that Pax6 interacts with the so-called BAF complex, which is known to modify chromatin structure – and that this interaction determines the neuronal fate of the neural stem cell progeny,” explains Dr. Jovica Ninkovic, the first author on the new paper.
The BAF complex controls gene expression by altering the accessibility of the genomic DNA to transcription factors. The interaction between Pax6 and BAF in neuronal progenitors thus causes local changes in chromatin structure that enable the activation of specific genes which promote neuronal differentiation. “The interaction of Pax6 with BAF results in the activation of a set of three transcription factors, which cross-regulate one another. This network ensures that the level of expression of genes necessary for neuronal differentiation is sufficiently enhanced to stabilize neuronal fate even in an environment in which normally only glial cells develop,” says Ninkovic. Conversely, if either Pax6 or BAF is absent, the adult neuronal progenitors convert to different types of glial cells, depending on the local tissue environment, instead of adopting a neuronal fate.
Interestingly, the network of transcription factors activated by the interaction of Pax6 with the chromatin remodeling complex in adult neurogenic cells is not needed for neurogenesis in the developing brain where neuronal fate is the normal default fate, while no glial cells are generated at this stage yet. Thus, stabilization of neuronal fate by a cross-regulatory transcriptional network is a hallmark required only in the adult brain to overcome the gliogenic environment. With these findings, Götz and her colleagues have identified a molecular mechanism that is specifically required for the generation of new neurons in the adult brain. “This could form the basis for novel therapeutic interventions to stimulate neurogenesis in cases of nerve cell loss due to neurodegenerative disease or brain damage," says Ninkovic.
(Cell Stem Cell 2013) göd