A previously unknown function that regulates how stem cells produce different types of cells in different parts of the nervous system has been discovered.  The results improve our understanding of how stem cells work, crucial for our ability to use stem cells to treat and repair organs. 

The stem cells’ task is to create new cells to replace those that have aged or become damaged. Previous research has shown that stem cells give rise to different types of cells in different parts of the nervous system. This process is partly regulated by the so-called Hox genes, which are active in various parts of the body and work to give each piece its unique regional identity - a kind of GPS system of the body. But how does a stem cell know that it is in a certain region? How does it read the body’s GPS signals? And how is this information used to control the creation of specific nerve cells? 

In order to address these issues, Linköping University researchers Stefan Thor, professor of Developmental Biology, and graduate students Daniel Karlsson and Magnus Baumgardt, studied a specific stem cell in the nervous system of the fruit fly. It is available in all parts of the nervous system, but it is only in the thorax, or chest region, that it produces a certain type of nerve cells. To find out why this type is not created in the stomach or head region they manipulated the Hox genes’ activity in the fly embryo. 

Summary of Hox Pbx Meis and temporal control of NB 5–6 development
The NB 5–6 lineage is generated in all CNS segments, but the genetic pathway leading to Ap cluster formation is only triggered in the NB 5-6T lineages. Three separate mechanisms act to ensure this segment-specific event. In abdominal segments, the Pbx/Meis genes hth and exd act with Bx-C Hox genes to truncate the NB 5-6A lineage by triggering neuroblast cell cycle exit within an early temporal (Pdm) window. This occurs prior to generation of Ap cluster cells, and prior to progression into the Cas/Grh late temporal window. In thoracic segments, the absence of Bx-C expression in the NB 5-6T neuroblast allows it to progress further and generate a larger lineage, thereby generating the Ap cluster cells. Importantly, this also allows for the lineage to progress into the Cas/Grh late temporal window. Combined with the expression of the thoracic Hox gene Antp, and increasing levels of Hth, this allows for integration of anteroposterior and temporal cues and the specification of Ap cluster cells into Ap cluster neurons, primarily by the activation of the critical Ap cluster determinant col. Grh plays a postmitotic role in specifying the Ap4/FMRFa cell fate. In anterior segments, the NB 5–6 lineage, although varying in size when compared to thoracic segments, does contain a Cas window. However, the absence of Antp expression, coupled with weak or absent expression of the late temporal gene grh, prevents specification of Ap cluster neurons.  Credit: Linköping University

It turned out that the Hox genes in the stomach region stop the stem cells from splitting before the specific cells are produced. In contrast, it was found that the specific nerve cells are actually produced in the head region, but that here the Hox genes turn them into another, unknown, type of cells. Hox genes can exert their influence both on the genes that control stem cell division behaviour and on the genes that control the type of nerve cells that are created.

“We constantly find new regulating mechanisms, and it is probably more difficult than previously thought to routinely use stem cells in treating diseases and repairing organs”, says Stefan Thor. 

Citation: Karlsson D, Baumgardt M, Thor S (2010), 'Segment-Specific Neuronal Subtype Specification by the Integration of Anteroposterior and Temporal Cues', PLoS Biol 8(5): e1000368. doi:10.1371/journal.pbio.1000368