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Project G

Project G

 

 

Name:

Prof. Dr. Andreas Kispert

 

Institution:

Institute of Molecular Biology

 

Telephone:

0049-511-532-4017

 

Email:

kispert.andreasmh-hannover.de

 

Research focus:

Our research focuses on the genetic control mechanisms governing vertebrate organ development using the mouse and the chicken as model organisms. More specifically, we are interested in gaining a better understanding of the cellular and molecular processes crucial in the development of mesodermally derived organs including limbs, heart, kidney, muscles and skeleton.

 

We are using all techniques of modern cell and molecular biology in addition to embryological manipulations in both mouse and chick as well as transgenics and targeted gene disruption to gain information on the mode of action of genes in vivo and in vitro.

 

A major focus of our work lies in the analysis of signaling proteins and of transcription factors of the Tbx-gene family in organogenesis. In future, another focus of our work will be the elucidation of the genetic control of epicard and coronary vessel formation.

 

In a cooperative effort we also work on the characterization of human kidney disease genes. Our group is located in the Institute of Molecular Biology in the theoretical department of Hannover Medical School. We are a small but highly dedicated group. We are seeking students and co-workers with a strong commitment to research and an ambitious work ethics. We promise excellent supervision with profound practical and theoretical training.

 

Projects:

Projects on Tbx gene function in organogenesis

 

T-box (Tbx) genes encode transcription factors characterized by a conserved DNA-binding domain, the T-box. Mutational analysis in mouse, natural mutations in humans (DiGeorge-Syndrome, Ulnar-Mammary-Syndrome, Holt-Oram-Syndrome) and gain-of-function approaches in chick have revealed important roles of these gene family in gastrulation, in heart and limb development. Using various methods including data base searches, low stringency screens and degenerate PCR approaches we have identified several new members of the Tbx gene family, including Tbx8, Tbx18 and Tbx20, in mouse and in chicken and have analyzed their expression during embryogenesis. We will continue to search for novel mouse Tbx genes and analyze the function of the known ones.

 

1. Projects on Tbx gene function in organogenesis T-box (Tbx) genes encode transcription factors characterized by a conserved DNA-binding domain, the T-box. Mutational analysis in mouse, natural mutations in humans (DiGeorge-Syndrome, Ulnar-Mammary-Syndrome, Holt-Oram-Syndrome) and gain-of-function approaches in chick have revealed important roles of these gene family in gastrulation, in heart and limb development. We have identified several new members of the Tbx gene family, including Tbx8, Tbx18, Tbx20 and Tbx22 in mouse and in chicken and have analyzed their expression during embryogenesis. The projects will deal with the functional characterization of these Tbx genes and their gene products in mouse organ development(somite and vertebral column, heart, limb). Mouse knockout mutants will be analyzed histologically and molecularly to gain insight in the primary function during development. Gain-of-function experiments shall provide further information on the genes regulated by these transcription factors.

 

2. Projects on epicard development The function of the vertebrate multi-chambered heart critically depends on a constant blood supply by the coronary vasculature. Coronary vasculature derives from an extracardiac source, the (pro-) epicardium, during embryogenesis. In this project we will try to lay ground for a more thorough understanding of coronary vasculature development in the mouse embryo by generating tools and reagents to analyze this process. We will specifically focus on early development of coronary vessels, i.e. epicardial development. First, we would like to develop tools for the functional analysis of epicardially expressed genes both in vitro and in vivo. A GFP knock-in in the Tbx18 locus shall provide GFP labeling of living epicardial cells. We want to establish an in vitro system of epicardial development based on primary cultures of epicardial precursor cells. A major point here will be elaboration of gene transfer systems in epicardial precursor cells by viral vectors to establish functional gene silencing within them. Second, we want to generate a collection of epicardially expressed genes by microarray analysis of the transcriptome of epicardial cells. This shall provide markers to more carefully describe epicardial development, and identify candidate genes for functional analysis in this process.

 

Group members:

Andreas Kispert, group leader

Marianne Petry, technician

Antje Bürger, postdoc

Markus Bussen, PhD student

Manvendra Kumar Singh, PhD student

Tran Tuoc, PhD student

Christian Roehr, PhD student (medicine)

 

Methods:

All standard molecular biology methods:

Cloning, DNA preparation, plasmid, phage and cosmid work

 

RNA work:

Isolation, in vitro synthesis, Northern blotting, in situ hybridisation on sections and whole mounts.

 

Protein work:

In vitro translation, SDS gel electrophoresis, IP, immunohistochemistry, gel shift assays and other DNA- protein interaction methods.

 

Cell culture:

Cultures cells lines, primary cell lines, ES cells, organ culture.

 

Animal related work:

Mouse: embryo isolation, cell, tisssue and organ isolation, manipulation and culture, husbandry.

Transgenic techniques, ES cells and Knockout technology

Chicken: embryo isolation, in ovo and in vivo embryonic manipulations

Key References:

Olbrich, H., Häffner, K., Kispert, A., Völkel, A., Volz, A., Sasmaz, G., Lehrach, H., Konietzko, N., Zariwala, M., Knowles, M., Mitchison, H., Chung, E., Hildebrandt, F., Sudbrak, R. and Omran, H. (2002). Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nature Genetics 30,143-144.

 

Kraus, F., Haenig, B. and Kispert, A. (2001). Cloning and expression analysis of Tbx18. Mech. Dev. 100, 83-86.

 

Kraus, F., Haenig, B. and Kispert, A. (2001). Cloning and expression analysis of the mouse T-box gene Tbx20. Mech. Dev. 100, 87-91.

 

Leitges, M., Neidhardt, L., Haenig, B., Herrmann, B.G. and Kispert, A. (2000). The paired homeobox gene Uncx4.1 specifies pedicles, transverse processes and proximal ribs of the vertebral column. Development 127, 2259-2267.

 

Vainio, S., Heikkila, M., Kispert, A., Chin, N. and McMahon, A.P. (1999). Female development in mammals is regulated by Wnt-4 signalling. Nature 397, 405-409.

 

Herrmann, B.G., Koschorz, B., Wertz, K., McLoughlin, K.J. and Kispert, A. (1999). A protein kinase encoded by the t complex responder gene causes non-mendelian inheritance. Nature 402, 141-146.

 

Kispert, A., Vainio, S. and McMahon, A.P. (1998). Wnt-4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney. Development 125, 4225-4234.

 

Kispert, A., Koschorz, B. and Herrmann, B.G. (1995). The T protein encoded by Brachyury is a tissue specific transcription factor. EMBO J. 14, 4763-4772.

 

Kispert, A. and Herrmann, B.G. (1993). The Brachyury gene encodes a novel DNA-binding protein. EMBO J. 12, 3211-3220, EMBO J. 12, 4898-4899.

 

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