Treier Group (Visiting)

Previous and current research

The specification of cell types during organ development has been studied intensively over the last decade. The future challenge is to understand how these different cell types function in a concerted action within an organ to fulfill its physiological task, and ultimately how mammalian physiologyis orchestrated to allow an organism to survive.

We employ mouse genetics to study various aspects of mammalian physiology, from the single cell stage to the complex interplay between organs that allow an organism to maintain energy homeostasis.

Stem/progenitor cell populations constitute the basic building units from which organs and whole organisms are created.We have identified with the transcriptional regulator, Sall4, one of the key players that is required to maintain the pluripotency state of embryonic stem cells. Sall4 is highly expressed in the inner cell mass (ICM) of a blastocyst which will give rise to the embryo properand the primitive endoderm.We could demonstrate that Sall4 is essential for self-renewal of embryonic stemcells as well as progenitor cells of the primitive endoderm derived from the ICM. We are currently employing genetic and biochemical methods to understand the regulation and functionof this important player in stem cell biology in greater detail.

At the organ level our research is mainly focussed on the kidney.We are interested in both the development of the organ as well as the physiological functions the kidney has to perform to maintain homeostasis at the organismal level. Many life-threatening inherited genetic disorders manifest themselves as malfunctions of the kidney, a particular example being polycystic kidney disease (PKD), which affects an estimated 13million people worldwide regardless of sex, age, race or ethnic origins (www.pkdcure.org). Whereas PKD leads to an enlargement of the organ through uncontrolled growth, another debilitating kidney syndrome is nephronophthisis, in which the kidneys shrink. Both syndromes are believed to result from aberrant signalling of an ancient organelle present on most kidney cells called the cilium, the sensor that allows kidney cells to react to changes in physiological parameters within the blood and urine (see figure).With the Glis family of transcriptional regulators, we have identified molecular players that are involved in transmitting the signal from the cilium to the nucleus, allowing kidney cells to respond to changes in their environment.We are now investigating at the molecular level how signal transmission is regulated through post-translational modifications.Understanding cilia signalling in general will have implications for many other human diseases, like for example Bardet-Biedel syndrome, that are caused by malfunctioning of this organelle.

The ultimate challenge in systems biology is to understand mammalian physiology. For any living organism, maintaining energy homeostasis is the central task for survival.We are particular interested in the neuronal circuits in the central nervous system (CNS) that are regulating energy balance.We have identified the brain-specific homeobox protein Bsx as an essential player in the regulation of food intake and locomotor activity, the two main components that determine energy homeostasis.We are currently investigating how higher brain centres interact with peripheral signals that signal satiety and hunger to regulate our drive to eat. In light of the obesity pandemic resulting in metabolic syndrome with its complications like type 2 diabetes, the understanding of the molecular mechanisms maintaining energy homeostasis has gained one of the highest priorities.

Future projects and goals

Transcriptional regulators will continue to be central to our investigation.Many can directly sense environmental cues and as a consequence alter the transcriptional readout from our individual genetic blueprint.With a series of mouse models for human diseases that we have created over the years, we are now in a position to dissect even complicated physiological questions at the organismal level. In parallel, we have started to look at how metabolism influences degenerative processes to open new avenues for pharmacological treatments in regenerative medicine.