FRAXA Research Foundation - finding a cure for Fragile X

Fragile X Mutant Mouse Facility

David L. Nelson, Ph.D.
Principal Investigator
Baylor College of Medicine
Houston

FRAXA Awards:
  $60,000 in 2010 (Mutant Mouse Resource)
  $60,000 in 2009 (Mutant Mouse Resource)
  $40,000 in 2006
  $70,000 in 2002 (fellowship for Ruiting Zong, PhD)
  $60,000 in 1998 (fellowship for Laura Kirkpatrick, PhD)

by David Nelson, 1/2009

Through generous funding by FRAXA Research Foundation, a Fragile X Mutant Mouse facility has been established at Baylor College of Medicine. A list of mouse strains is provided here. As the facility gets up to speed, it is anticipated that in addition to breeding pairs, animals in numbers sufficient for experimentation as well as tissues will be provided, reducing the need for others to establish their own colonies. These latter services may require small fees if demand becomes significant. Requesting groups will be expected to reimburse for shipping charges and for some strains, there will be a Materials Transfer Agreement with the BCM Licensing group. Please contact David Nelson directly at nelson@bcm.edu to request mice or with any questions or concerns.

Assessing the role of development in Fragile X syndrome using inducible mouse models of FMR1

by David Nelson, 10/2006

The aim of this project is to generate additional mouse models of fragile X syndrome to study neuronal and behavioral aspects of the mice that have had the FMR1 protein removed or replaced at various time points during development of the animal. Deletion of Fmr1 in mice during embryonic and postnatal development will be achieved by in vivo application of an inducible enzyme that can delete the Fmr1 gene. A similar approach will allow restoration of full Fmr1 expression from a version of the gene that has an interfering DNA that can be removed by the same enzyme.

Using these inducible Fmr1 genes, we will determine whether the differences observed between mice lacking Fmr1 and normal mice result from an ongoing lack of FMRP expression or are due to lasting consequences of the absence of FMRP during development. We propose to investigate whether the restoration of FMRP in fragile X mice after birth can rescue the abnormal neuronal and behavioral phenotypes and whether loss of FMRP in later stages can cause those phenotypes. Mice with modifiable Fmr1 loci are already created, but need to be characterized. Phenotypes to be studied are sleep/wake cycles and other behaviors, electrophysiology in the brain and mis-regulation of specific genes such as MAP1B. Development of these new mouse models of Fmr1 will provide additional tools suitable for testing potential therapies. Creation and characterization of these mouse models will also allow other groups to study developmental requirements of additional phenotypes.

by David Nelson, 7/2002

This study is designed to improve methods for defining the function of FMRP. We are developing new mouse models for Fragile X in which we can selectively express the Fragile X protein, FMRP, at different times and in different parts of the brain. These mice will be engineered such that we can regulate the amount of FMRP produced in their cells by feeding the animals a common antibiotic, tetracycline. Tissue-specific expression of FMRP will be provided by the human FMR1 promoter so that the mice will show a similar pattern of expression for FMR1 as that in humans. We will also construct cellular models that conditionally express FMRP. These models will be used to study the developmental role of FMRP and determine the potential for therapeutic approaches to Fragile X syndrome.

Our models will also provide tools to help identify and characterize mRNA targets of FMRP in cells and tissues. Recently, several mRNA targets of FMRP have been identified. However, which of these is altered by changes in FMRP abundance in living animals? How does FMRP regulate the activity of its mRNA targets? To characterize some of these targets, we have created inducible FMRP in neuronal cell lines (N2a) that conditionally express FMRP. Using these cell lines together with YAC FMR1 transgenic mice as a complementary model, we expect to validate candidate target mRNAs and begin to unravel the consequences of absence of FMRP. These models should also provide the ability to measure effects of therapeutic interventions.