Research Profile Peter Mombaerts, M.D., Ph.D.

Peter Mombaerts, M.D., Ph.D.
  • M.D., Katholieke Universiteit Leuven, Leuven, Belgium, 1987
  • Ph.D. in Biology/Immunology, Massachusetts Institute of Technology, Cambridge, MA, USA, 1992.
    Advisor: Susumu Tonegawa
  • Postdoc in Neurobiology, Columbia University,
    New York, NY, USA, 1993-1995.
    Advisor: Richard Axel
  • Assistant Professor (1995-2001), Associate Professor (2001-2003), and Professor (2003-2007), The Rockefeller University, New York, NY, USA
  • Director, Department of Molecular Neurogenetics, 2006, full-time since January 2008

The Olfactory System of the Mouse

Mouse generated by nuclear transfer from an olfactory sensory neuron that expressed the odorant receptor M71.

Odorant receptor gene choice

By nuclear transfer of OSNs that express a particular OR, we have demonstrated that OR gene choice does not involve irreversible DNA rearrangements in the genome. We have provided evidence that is inconsistent with the hypothesis of the function of a sequence called the H element as a trans-acting enhancer for OR promoters throughout the genome. We found that the promoters for the OR genes M71 and MOR23 are proximal and short, and that they contain binding sites for homeodomain proteins and O/E transcription factors. We have shown that OR genes of the so-called class II (the majority of OR genes) are dependent on the LIM-homeodomain protein Lhx2 for their expression, either directly or indirectly via maturation of the OSNs. By contrast, class I OR gene expression is independent of Lhx2.

Dorsal view of a wholemount of both olfactory bulbs of a mouse in which olfactory sensory neurons that express the odorant receptor M72 are stained blue. The axons of these neurons terminate and coalesce into one glomerulus per half-bulb.

Axonal wiring

We have developed genetic approaches in mice to visualize or manipulate a population of OSNs that express the same OR, using gene targeting in embryonic stem cells. A typical design is the co-expression of an axonal marker such as taulacZ or tauGFP with an OR gene, which is made possible at the translational level by virtue of an internal ribosome entry site. Gene-targeted mutations in the OR coding sequence, such as its replacement by the coding sequence of another OR, have collectively demonstrated that the OR is instrumental in axonal coalescence itself, and in determining the approximate site in the glomerular layer of the olfactory bulb where axonal coalescence occurs. An extensive series of gene-targeted mice led us to propose a model of homophilic interactions between ORs or OR-containing membrane complexes as a fundamental mechanism of OR-dependent coalescence of axons into glomeruli. We have recently found that there are two OSN types, which express either class I or class II ORs, and that these OSN types are determinants of axonal wiring, operating at a level higher than the ORs.

Dorsal view of a both olfactory bulbs of a mouse in which all olfactory sensory neurons express a fluorescent indicator for synaptic transmission, synaptopHluorin. The mouse has been exposed to the odorant butanal. Glomerular activation is depicted in pseudocolors, from green (low) over blue and yellow to red (high).

Olfactory coding

We have shown that OSNs that express the same OR respond to the same odorous ligands, and that genetic replacement of the OR coding sequence shifts the odorant response pattern accordingly. We have identified odorous ligands for several mouse ORs. We observe, however, a substantial heterogeneity in the electrophysiological responses to a given odorant among OSNs that express the same OR. We have engineered mice in which all mature OSNs express an indicator of synaptic activity, permitting us to record in vivo responses to odorants in the olfactory bulbs of anesthetized mice.

Cross-section through the vomeronasal organs of a mouse. Staining by in situ hybridization with Gαi2 (green) and Gαo (red) shows that the epithelium of the VNO consists of two types of neurons.

Vomeronasal receptors and pheromones

The vomeronasal organ (VNO) in the nasal cavity of the mouse is specialized in the detection of pheromones, but it is responsive to other chemosensory stimuli as well, and conversely, the main olfactory epithelium can also detect compounds with pheromonal effects. The vomeronasal sensory neurons (VSNs) of the VNO express G-protein coupled receptors of two other large gene families, which are unrelated to ORs: the V1Rs and V2Rs. With our genetic approach we have demonstrated that axons of VSNs that express a given V1R or V2R coalesce into multiple, smaller glomeruli in the accessory olfactory bulb. We have shown that a given VR gene is expressed from one allele in an individual VSN. By generating mice that lack a cluster of 16 V1R genes via chromosome engineering, we have provided in vivo evidence for a role of V1Rs in pheromone behaviors. We have discovered a family of nine non-classical class I Major histocompatibility genes, H2-Mv genes. These genes are expressed only in the VNO, specifically in VSNs that express V2R genes, and in particular combinatorial patterns. Their function and regulation remain elusive.

Cloning mice by nuclear transfer

We have reported the cloning of mice by nuclear transfer from embryonic stem cells. Conversely, we have generated embryonic stem cell lines from blastocysts produced by nuclear transfer. We have shown that OR gene choice is reset upon nuclear transfer with OSNs. We have cloned mice from adult skin cells. We have demonstrated the feasibility of nuclear transfer with somatic cells that were frozen for prolonged periods of time without cryoprotectant.

METHODOLOGIES 

  • Gene targeting in embryonic stem cells
  • Transgenesis by pronuclear injection
  • Cloning by nuclear transfer
  • Fluorescent in situ hybridization and immunohistochemistry
  • Confocal and two-photon microscopy
  • Intrinsic signal imaging
  • Calcium imaging
  • Patch-clamp electrophysiology
  • Olfactometry

Contact:

Max Planck Institute of Biophysics

Peter Mombaerts, Director
Department of Molecular Neurogenetics

Phone: +49 (0) 69 6303-4000

E-mail: peter.mombaerts(at)biophys.mpg.de

Dept. of Molecular Neurogenetics:

Group Members:

Postdocs

  • Sachiko Akiyoshi
  • Zhaodai Bai
  • Anna D'Errico
  • Markella Katidou
  • Mona Khan
  • Kiavash Movahedi
  • Marta Parrilla
  • Masayo Omura
  • Evelien Vaes
  • Martin Vogel

Graduate students

  • Diane Bissen
  • Olaf Bressel
  • Isabelle Chang
  • Andrea Degl'Innocenti
  • Anna Holl
  • Jiangwei Lin
  • Bassim Tazir
  • Bolek Zapiec
  • Zhen Zeng

Scientific support staff

  • Elisabeth Strohmayr

Lab manager

  • Guido Haschke

Support staff

  • Tobias Burbach
  • Annelie Götz
  • Stefanie Kranz
  • Mandy Kurth
  • Rebecca Laschet
  • Florian Lindenblatt
  • Bartos Machert
  • Susanne Reichert
  • Carolin Sallermann
  • Rebecca Worgull
  • Ali Yarali