The Svedberg Award 2003

Johan Ericson
Department of Cell and Molecular Biology, Karolinska Institute


Specification of Cell Fate in the Developing CNS

Background
After undergraduate studies in molecular biology at Umeå University, I began my graduate training in 1990 in Thomas Edlund’s laboratory at the Department of Microbiology, Umeå University. In his laboratory, I became exposed to general questions related to how cells can acquire their unique functional properties during embryonic development, and in January 1995 I presented a thesis examining the establishment of cell diversity in the developing anterior pituitary and in the ventral CNS. I thereafter pursued post-doctoral studies in Thomas M. Jessell’s laboratory at Columbia University in New York. In Tom’s lab, I became interested into mechanisms that control the patterned generation of neuronal subtypes along the dorsal-to-ventral (DV) axis of the developing spinal cord, and I have continued to work along this line of research also after establishing my own laboratory at the Karolinska Institute in 1999.

Research
The functional basis of the central nervous system (CNS) depends on the precise spatial and temporal generation of distinct functional types of neurons during embryonic development. Neurons acquire their identity in response to local signals that provide positional information to dividing neural progenitor cells along the DV and anterior-to-posterior (AP) axes of the neural tube. Our research has been directed at understanding the cellular and molecular mechanisms that control the formation of neuronal cell diversity in the developing spinal cord and brainstem. These axial levels are the simplest and most well characterised subdivisions of the CNS, and thus represent a suitable model system to approach basic principles of neural development.

We have shown that the secreted protein Sonic hedgehog (Shh) have a central role in the induction of most neurons generated in the ventral half of the CNS, and further that Shh act as a gradient morphogen which induce different types of neurons at different concentration thresholds. This observation raised the issue how neural progenitors can perceive, and respond differently, to small changes in the ambient concentration of Shh. We found that a key role for Shh in this process is to control the spatial expression of a set of homeodomain (HD) transcription factors in responding progenitor cells, establishing a combinatorial code of homeodomain protein expression that control the specification of distinct neuronal subtypes at defined positions. Unexpectedly, the ability of these HD proteins to induce specific neuronal subtypes depend their ability to act as transcriptional repressors. In contrast to conventional activator models of cell fate specification, this finding places derepression strategies at the heart of neuronal differentiation in the developing CNS.

In addition to these studies of cell patterning along the DV axis, we have begun to investigate how DV patterning may be integrated with patterning mechanisms that operates along the AP axis and also over time. By examining the generation of motor neurons and serotonergic neurons in the brainstem, we have recently shown that close interactions between DV and AP patterning genes not only control spatial, but also temporal, aspects of neuronal fate specification. These data suggest that mechanisms that underlie the generation of different neurons in space and over time are tightly interconnected.

Selected references:
Pattyn, A., Vallstedt, A., Dias, J., Sander, M., and Ericson, J. (2003). Complementary roles for Nkx6 and Nkx2 class proteins in the establishment of motoneuron identity in the hindbrain. Development 130, 4149-59.
Pattyn, A., Vallstedt, A., Dias, J., Abdel Samad, O., Krumlauf, R., Rijli, F.M., Brunet, J-F., and Ericson, J. (2003). Coordinated temporal and spatial control of motor neuron and serotonergic neuron generation from a common pool of CNS progenitors. Genes Dev 17, 729-737.
Persson, M., Stamataki, D., te Welscher, P., Andersson, E., Rüther, U., Ericson, J., and Briscoe, J. (2002). Dorsal-Ventral Patterning of the Spinal Cord Requires Gli3 Transcriptional Repressor Activity. Genes Dev 16, 2865-78.
Vallstedt, A., Muhr, J., Pattyn, A., Andersson, E., Pierani, A., Mendelsohn, M., Sander, M., Jessell, T.M., and Ericson, J. (2001). Different levels of repressor activity assign redundant and specific roles to Nkx6 genes in motor neuron and interneuron specification. Neuron 31, 743-55.
Muhr, J., Andersson, E., Persson, M., Jessell, T.M., and Ericson, J. (2001). Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube. Cell 104, 861-873.
Briscoe, J., Pierani, A., Jessell, T. M., and Ericson, J. (2000). A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 101, 435-445.
Briscoe, J., Sussel, L., Serup, P., D.Hartigan-O´Connor, D., Jessell, T.M., Rubenstein, J.L.R., Ericson, J. (1999). Homeobox gene Nkx2.2 and specification of neural identity by graded Sonic hedgehog signalling. Nature 398, 622-627.