Abstracts (complete list) - Wissenschaft Online

Alexander Gerbaulet, Julia Scholten, Thomas Krieg, Karin Hartmann, Axel Roers
Generation of a Mouse Model for Mastocytosis
Mastocytosis is characterized by infiltration of abnormal numbers of mast cells into skin
and internal organs. The clinical spectrum is broad ranging from mild increases in
cutaneous mast cell numbers to severe forms of mast cell leukaemia. The disease is
associated with activating somatic point mutations of the receptor tyrosine kinase Kit,
however, the relevance of these mutations for the different forms of the disease is
unclear. We generated a transgenic mouse model based on a 200 kb BAC containing the
entire kit gene. Two modifications were introduced: 1) the activating point mutation
D814V and 2) a floxed “stop” cassette, allowing Cre/LoxP-mediated control of transgene
expression. The construct was pronucleus-injected and founder animals transmitted the
transgene in the germline. Kit D814Vflox transgenic mice were bred to the hCMV (deleter)-
Cre-line for ubiquitous deletion of the stop element, which should result in expression of
the mutated kit under the control of the kit promotor elements contained in the
transgene. Kit D814Vflox deleter-Cre double transgenic mice were born in numbers
significantly lower than expected indicating a high frequency of lethality during
gestation. The few animals born alive displayed a diverse spectrum of phenotypes.
While some mice showed cutaneous mastocytosis of variable intensity, others
developed various additional neoplasms including malignant mast cell tumors. We are
presently investigating the cause of embryonic death in the majority of Kit D814Vflox
deleter-Cre double transgenic embryos, the effect of Kit D814V expression in mature mast
cells of Kit D814Vflox Mcpt5-Cre double transgenic mice and the induction of Kit D814V
expression in adult Kit D814Vflox Mx-Cre double transgenic mice.