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Treier Lab

Genetics of Metabolic and Reproductive Disorders

Profile

Our research is focused on the regulation of mammalian physiology by genetic variation. Transcriptional regulators constitute the cornerstones of our research activities.

In particular, we try to understand how metabolic changes influence the epigenetic landscape to modulate the transcriptional response in a quest for maintaining body homeostasis during adaptation to novel environmental conditions. We utilize a plethora of mouse models for human diseases that we create ourselves that allow us to dissect even complicated physiological questions at the organismal level.

  • Stem cells - the magic path to immortality?
  • Can a kidney cilium "smell" glucose?
  • Does a Western diet make us lazy?
  • A girl is a girl - or isn't (s)he?

Fundamental questions that, in spite of all the scientific progress that has been made, are still unanswered.

Sexual reprogramming that is induced by silencing of the FoxL2 gene; In the left panel is an ovary of a wildtype female mouse showing the typical female granulosa cells (close-up: lower left). After knock out of FoxL2 (right panel) in these cells, they take on the characteristics of Sertoli cells (close-up: lower right) that, however, are normally found in testes of male mice.

In our group, we study various aspects of mammalian physiology, from the single cell stage to the complex interplay between organs, that enable an organism to maintain homeostasis. Step by step we move forward in understanding how mammalian physiology is orchestrated to allow an organism to survive in a changing metabolic environment.

To gain insight into our work start browsing our homepage.

If you get inspired and want to join us in our quest, check out the job options or contact us directly!

 

 

 

                                                    published in Cell 2009

Team

Research

Our research is focused on metabolic and reproductive processes and their genetic regulation. Transcriptional regulators are at the center of our investigations.

In particular, we have started to look how metabolic changes influence the epigenetic landscape by modulating the transcriptional responses to adapt to environmental conditions.

With a series of mouse models for human diseases that we created over the last years, we are now in a position to dissect even complicated physiological questions at the organismal level.

These are the fields we are currently working on:

Energy homeostasis an​​​​​d eating behavior

The ultimate goal for any living organism is to maintain energy homeostasis in its quest to survive.

We are particularly interested in the neuronal circuits of the central nervous system (CNS) that are involved in the (dys)regulation of energy homeostasis in obesity. With the brain-specific homeobox protein BSX we have identified an essential player marking a neuronal network within the hypothalamus that orchestrates eating behavior, sleep and higher cognitive functions.

“You think what you eat”!

It is our goal to unravel the reciprocal interactions between hormonal signals and higher cognitive functions in the regulation of eating behavior. An important aspect of our work will rely on a state-of-the-art method in neuroscience: CLARITY.

 

Stem cells, transcription factors and epigenetic regulation

Epigenetic regulation of cell type determination

Stem/progenitor cell populations constitute the basic building units from which organs and whole organisms are created.

We identified the transcriptional regulator SALL4 as a key player that is required to maintain the pluripotency state of embryonic stem cells. SALL4 is highly expressed in the inner cell mass (ICM) of the blastocyst that gives rise to the embryo and the primitive endoderm.

We employ omics technologies to understand the regulation and function of this central player in stem cell biology. Using a biotin/streptavidin system we have unraveled the SALL4 protein complex and its protein interaction network in embryonic stem cells. In addition, we have identified the chromosomal localization pattern of these proteins by chromatin immunoprecipitation in combination with high-throughput parallel sequencing (ChIP-Seq).

Currently, we determine the epigenetic alterations that result from changes of these protein complex activities upon growth hormone factor signaling.

This work was part of the Priority Program SPP 1356 "Pluripotency and Cellular Reprogramming" of the German Research Foundation

 

Sexual reproduction

 

XX = girl and XY = boy

That's what we learnt in school, right? However, there is more to gender phenotype than meets the eye.

We have recently uncovered the molecular mechanism underlying sexual maintenance in mammals revealing an unexpected and fascinating plasticity through a Yin and Yang relationship between two genes, whose expression is mutually exclusive. These two genes are called FOXL2 and SOX9, both transcriptional regulators. 

While SOX9 protein expression is abundant in males at all stages of development, it has to be continuously suppressed in adult females to stabilize the female phenotype and to prevent trans-differentiation of the ovaries into testes (see Uhlenhaut et al, Cell 2009). 

Yin and Yang relationship of FOXL2 and SOX9 in the maintenance of sexual identity in mammals

During initial phases of sex determination, SRY up-regulates SOX9 expression, and subsequent positive autoregulatory loops involving SOX9 itself. Together with FGF9 and prostaglandin D2 signaling, this activates and maintains Sox9 expression in male gonads, whereas ß-catenin, stabilized by WNT4 and RSPO1 signaling, suppresses SOX9 expression in female gonads.

After birth ß-catenin activity declines and thus in adult female gonads, FOXL2 and estrogen receptors are required to actively repress SOX9 expression to ensure female somatic cell fate.

The transcriptional repression of SOX9 by FOXL2 and estrogen receptors is necessary throughout the lifetime of the female to prevent transdifferentiation of the somatic compartment of the ovary into a testis.

 

 

Methods

Some of the state-of-the-art techniques used in our lab involve:

  • Generation of transgenic mouse models by laser assisted micromanipulation of mouse embryos >>> Watch the video!
  • Mouse metabolic phenotyping
  • In vivo biotinylation to study protein function
  • Fluorescence and confocal microscopy
  • CLARITY

 

Publications

Selected Publications

Uhlenhaut N, Jakob S, Anlag K, Eisenberger T, Sekido R, Kress J, Treier AC, Klugmann C, Klasen C, Holter N, Riethmacher D, Schütz G, Cooney A, Lovell-Badge R & Treier M (2009). Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 139:1130-1142.

[PDF] [Pubmed]

Attanasio M, Uhlenhaut NH, Sousa V, O’Toole JF, Otto E, Anlag K, Klugmann C, Treier AC, Helou J, Sayer JA, Seelow D, Nürnberg G, Becker C, Chudley AE, Nürnberg P, Hildebrandt F & Treier M (2007) Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nature Genetics 39:1018-1024.

[PDF] [Pubmed]

Sakkou M, Wiedmer, P, Anlag, K, Hamm, A, Seuntjens, E, Ettwiller, L,Tschop, M & Treier M (2007). A Role for Brain-Specific Homeobox Factor Bsx in the Control of Hyperphagia and Locomotory Behavior. Cell Metabolism 5:450-463

[PDF] [Pubmed]

Elling, U., Klasen, C., Eisenberger, T., Anlag, K. & Treier, M (2006). Murine inner cell mass derived lineages depend on Sall4 function. PNAS 103(44), 16319-24.

[PDF] [Pubmed]

Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier AC, Treier M (2004). The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development 131(4):933-42.

[PDF] [Pubmed]

Treier M, Gleiberman AS, O'Connell SM, Szeto DP, McMahon JA, McMahon AP, Rosenfeld MG (1998). Multistep signaling requirements for pituitary organogenesis in vivo. Genes & Development 12(11):1691-704.

[PDF] [Pubmed]

Treier M, Staszewski LM, Bohmann D (1994). Ubiquitin-dependent c-Jun degradation in vivo is mediated by the delta domain. Cell 78(5): 787-98

[PDF] [Pubmed]

Prof. Dr. Mathias Treier
Prof. Dr. Mathias Treier
Group Leader
Contact
Phone: 9406-3460
Max-Delbrück-Centrum für Molekulare Medizin (MDC)
Robert-Rössle-Str. 10
13092 Berlin, Deutschland
Building 89, Room 2.01