Stefan Thor  received his undergraduate degree in Biology from Umeå University, Sweden, in 1988. He trained in developmental biology as a graduate student with Thomas Edlund, also at Umeå University and received his PhD in 1994. His post-doctoral training in Drosophila developmental biology was conducted at the Salk Institute, with John B. Thomas. In 1999, he moved to Harvard Medical School and established his first independent lab, in the Department of Neurobiology. In 2004, he moved back to his native country Sweden, and is currently a Professor of Developmental Biology at Linköping University. In 2013, he was elected into the Swedish Royal Academy of Sciences. He has a longstanding interest in cell specification, and earlier work focused on the transcriptional codes that dictate unique cell fate in the nervous system. Current research in the lab focuses on proliferation control in the developing nervous system, and how proliferation is integrated with cell fate decisions to ensure that the proper number of each cell type is generated.

Controlling cell fate and cell number in the developing nervous system

Specification of the myriad of unique neuronal sub-types found in the nervous system depends upon complex regulatory cascades. These involve spatial and temporal cues, as well as cell-type specific determinants, often acting in combinatorial codes to determine final cell fate. While some progress has been made with respect to the identification of several such genetic cascades, little is known about the molecular flow from spatio-temporal cues to final cell fate. To address this issue we are using the Nplp1 neuropeptide cells in the Drosophila ventral nerve cord; a subset of Apterous neurons, generated by thoracic neuroblast 5-6 (NB5-6T), as a model.

Nplp1 cell fate specification involves a cascade of different transcription factors and co-factors (TFs), which feed forward onto their specific downstream to ultimately specify the Nplp1 cell fate in a sequential combinatorial fashion. These involve positional TFs (Hox and Hox co-factors), temporal and sub-temporal TFs (Castor, Sqz and Nab), acting on a set of postmitotic cell fate determinants (terminal selector genes), which in turn act at later stages to dictate the final cell identity. We have identified the six key enhancers involved in the Nplp1 specification cascade and we have begun dissecting their organization by extensive in vivo studies. These involve mutant and misexpression analysis, enhancer mutagenesis, and ChIP-seq of the identified TFs. In addition, the CRISPR/Cas9 system is being used to delete specific enhancer regions for each gene in the regulatory cascade.

These studies reveal complex combinatorial molecular action of TFs to sequentially specify the unique Nplp1 cell fate, involving the integration of temporal and positional cues onto terminal selector genes in the NB5-6T neuroblast and post-mitotic neurons to ultimately determine final cell fate, evident by the final activation of the Nplp1 enhancer. To our knowledge, this study represents the first case where the molecular logic of spatial and temporal cues onto final and unique neuronal cell fate, within the detailed context of a well-mapped neuroblast lineage, has been resolved.