Our research aims to elucidate the key mechanisms of neurogenesis in the developing and adult brain. In contrast to organs such as the skin, the small intestine or the hematopoietic system, most cells in the adult mammalian nervous system are permanently postmitotic, such as the neurons and the oligodendrocytes, and are not turned over nor regenerated once they die. Neurogenesis persists only in very few regions of the adult mammalian forebrain, and neurons degenerated after acute or chronic injury are not replaced in the adult mammalian brain. To overcome this, we study neurogenesis when and where it works with the aim to reactivate these mechanisms and re-instruct neurogenesis after brain injury. Using our developmental knowledge about neurogenesis, we have pioneered the approach to generate new neurons by direct reprogramming from glial cells, first in vitro and then in vivo which has now become a world-wide very active field of research and an interesting approach for novel therapeutic approaches to brain repair (Barker et al., Nature 2018; Grade & Götz, Regen. Medicine 2017).
This approach has been inspired by our discovery that glial cells are the source of neurons in the developing brain (Malatesta et al., 2000). The ubiquitous glial cells in the developing brain are radial glia that generate the majority of neurons and glia during brain development (Malatesta et al., 2000; 2003; for review see: Götz et al., 2015; Götz in Neuroglia, ed. Kettenmann and Ransom; Borell and Götz, 2014; Taverna et al., 2014; Malatesta and Götz, 2013; Götz and Huttner, 2005). However, when neurogenesis ceases, radial glial cells also disappear in the mammalian brain and give rise to ependymal cells lining the brain ventricle. In a few regions of the mammalian brain – and more wide-spread in other vertebrates – neural stem cells persist into adulthood and function as source of ongoing neurogenesis. We therefore examine the mechanisms of how adult neural stem cells are specified during development (Pilz et al., Nature Comm. 2013; Falk et al., Neuron 2017) and how adult neurogenesis works in the neurogenic niches of the adult murine forebrain (Beckervordersandforth et al., Cell Stem Cell 2010; Ninkovic et al., Neuron 2010, Cell Stem Cell 2013; Calzolari et al., Nature Neuroscience 2015; Barbosa et al., Science 2015; Petrik et al., Cell Stem Cell; Lepko et al., EMBO J 2019), and compare these mechanisms to those operating during development (Camargo et al., Nature 2019; Cappello et al., Neuron 2016, Nature Genetics 2013; Stahl et al., Cell 2013; for review see: Falk and Götz, 2017; Götz et al., 2015; Ninkovic and Götz, 2013). Moreover, neurogenesis also persists in a more widespread manner in the adult zebrafish brain, where radial glial cells persist into adulthood (Adolf et al., 2006; Chapouton et al., 2008). We therefore compare mechanisms of adult neurogenesis in different species in collaboration with the Ninkovic lab.
In order to implement neurogenesis after brain injury, we examine the reaction and function of different glial cells in traumatic brain injury and neurodegenerative models (Frik et al., EMBO Rep. 2018; Heimann et al. Cerebral Cortex 2017; Bardehle et al., nature Neuroscience 2013; Sirko et al. Cell Stem Cell 2013; Dimou et al., JN 2008; for review see: Dimou and Götz, Physiological Reviews 2014). This work suggests that reactive astrocytes proliferate predominantly close to the blood vessels and perform beneficial functions there, like restraining monocyte invasion. Thus, other glial cells, postmitotic, neurotoxic astrocytes or oligodendrocyte progenitors may best be targeted to convert into neurons and interfere with scar formation at the same time.
In order to generate new neurons after brain injury in regions where no neurogenesis occurs (most of the adult mammalian brain), such as the cerebral cortex, we introduce neurogenic fate determinants in glial cells to convert these into neurons. We pioneered this approach using the transcription factor Pax6 in vitro (Heins et al., Nature Neuroscience 2002) and in vivo (Buffo et al., PNAS 2005) and then further developed it to prove the functionality of these neurons and generate different neuronal subtypes in vitro from murine (Berninger et al., JN 2007; Heinrich et al., PLOS Biol. 2010) and human cells (Karow et al., Cell Stem Cell 2012) and in vivo (Heinrich et al. Stem Cell Rep. 2014; Gascón et al., Cell Stem Cell 2016; Mattugini et al., Neuron 2019). Importantly, we also showed by transplanting neurons into a neuronal-subtype-specific lesion model that specific neuronal subtypes can be adequately replaced by acquiring the correct brain-wide input connectome and functional receptive field properties (Falkner et al., Nature 2016) thereby pioneering the field of neuronal replacement therapy.