Neural Development Group - Research Focus

 

In vitro modeling of human brain development

Monolayer cultures of pluripotent stem cell derived cortical progenitors expressing Otx2 (red) and Pax6 (green)We aim at establishing in vitro neural differentiation systems using pluripotent stem cells (PSC) to understand the molecular and cellular basis of human telencephalic development. As cortical development involves various local cell-cell interactions and internal self-organizing programs we will in addition to our highly standardized 2D cell culture system explore the potential of 3D culture systems to develop a layered "cortex" in vitro. These 3D methods have the potential to recapitulate developmental processes in a reasonably natural manner. Even with many steps ahead before we can fully recapitulate the complex features of human cortical development, PSC based culture systems open exciting new avenues to further shed light on human cortical development and to provide a substrate for understanding neurodevelopmental diseases.

Pluripotent stem cell derived 3D cortical cultures exhibit loop like structures

 

Cortical progenitors and associated disorders
Unlike the developing rodent cortex, the developing human cortex contains a massively expanded outer proliferative zone that is thought to account for the bulk of cortical neurogenesis. We will explore whether a PSC based human in vitro model can be used to further characterize the different types of progenitor cells known to be present in the human developing cortex in a normal and diseased context.

 

Migration of cortical neurons and associated disorders
Pluripotent stem cell derived ßIII-tubulin (green) positive neurons co-expressing the cortical layer specific transcription factor Ctip2 (red)The human cerebral cortex is a highly specialized and distinct six-layered structure. subserving critical functions that can be disrupted in developmental disorders. During normal cortical development neurons are generated in the cortical neuroepithelium and migrate radially to reach the cortex following an inside-outside gradient. We will investigate the molecular and cellular mechanisms underlying neuronal migration by using a human in vitro model applying PSCs as well as induced PSCs derived neurons from patients suffering from cortical developmental disorders such as lissencephalies. Here we will apply developed techniques such as a genetic lineage selection approach of young migratory neurons (Ladewig* Koch* et al., 2008) and established in vitro and in vivo migration assays (Ladewig*, Koch* and Brüstle, 2014).

 

Direct conversion
Induced neurons show neuronal mophology and expression of the neuronal markers ßIII-tubulin (green) and MAP2ab( red)Direct conversion of human fibroblasts into induced neurons is a potential new strategy for generating specific neuronal subtypes in vitro. Recent insights gained from studies of the developing human cerebral cortex are illuminating potential important transcription factors for the development of specific cortical neuronal subpopulations. Applying latest direct programming technologies we developed culture conditions for the efficient direct conversion of human fibroblasts into functional neurons (Ladewig et al., 2012; Ladewig*, Koch* et al., 2013). We will explore the potential of the direct conversion technology to directly convert human fibroblasts into specific cortical neuronal subtypes.