Transcriptional Regulation of the Fragile X Gene

With a $60,000 in grant from FRAXA Research Foundation, Dr. Justin Fallon and his team at Brown University studied systematic mapping of Fragile X granules in developing mouse brains, revealing a potential role for presynaptic FMRP in sensorimotor functions.

Justin Fallon, PhD, Brown University, FRAXA research grant
$60,000 Grant
Justin Fallon, PhD
Principal Investigator

Anne Booker
Graduate Student (2004-2005)

Brown University
2005-2006 FRAXA Research Grant
$60,000

 Results published in J Comp Neurol.

Akins MR, Leblanc HF, Stackpole EE, Chyung E, Fallon JR, 4/23/2012

Abstract

Loss of Fragile X mental retardation protein (FMRP) leads to Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism. Although the functions of FMRP and its homologues FXR1P and FXR2P are well studied in the somatodendritic domain, recent evidence suggests that this family of RNA binding proteins also plays a role in the axonal and presynaptic compartments. Fragile X granules (FXGs) are morphologically- and genetically-defined structures containing Fragile X proteins that are expressed axonally and presynaptically in a subset of circuits. To further understand the role of presynaptic Fragile X proteins in the brain we have systematically mapped the FXG distribution in the mouse central nervous system. This analysis revealed both the circuits and the neuronal types that express FXGs. FXGs are enriched in circuits that mediate sensory processing and motor planning – functions that are particularly perturbed in FXS patients. Analysis of FXG expression in the hippocampus suggests that CA3 pyramidal neurons utilize presynaptic Fragile X proteins to modulate recurrent but not feedforward processing. Neuron-specific FMRP mutants revealed a requirement for neuronal FMRP in the regulation of FXGs. Finally, conditional FMRP ablation demonstrated that FXGs are expressed in axons of thalamic relay nuclei that innervate cortex, but not in axons of thalamic reticular nuclei, striatal nuclei, or cortical neurons that innervate thalamus. Together, these findings support the proposal that dysregulation of axonal and presynaptic Fragile X proteins contribute to the neurological symptoms of FXS.

Project Plan by Anne Booker, 2/1/2005
Our laboratory is interested in the molecular mechanisms that regulate Fmr1 expression. Recently, we have developed a new model to study Fmr1 transcription in the central nervous system (CNS). We have shown that olfactory experience (smelling) bi-directionally regulates Fmr1 gene expression. Moreover, this regulation is highly dependent on developmental stage. In preliminary experiments we have observed that DNA methylation patterns in the Fmr1 promoter are correlated with the developmental changes in gene expression. We will investigate the transcriptional regulation of fmr1 using a combined molecular, cellular and biochemical approach in both in vitro and in vivo systems.

The main goal of this study is to discover the specific processes that are responsible for the bi-directional regulation of the fmr1 gene. There are several ways in which genes can be regulated. One aim is to identify transcription factors-proteins that bind to specific regions of DNA and promote the synthesis of messenger RNA. Second, recent studies have shown that epigenetic modifications — such as the methylation of a gene and histone acetylation — can also be influenced by both development and activity. Our preliminary data suggest that the fmr1 gene is regulated throughout development and following activity by these epigenetic modifications. We hypothesize that some transcription factors and epigenetic modifications are particularly important in early development, while others play a prominent role later in life.

Results from these studies will help us understand the normal function and regulation of Fmr1 in early childhood and in the adult. These insights could aid in the design of therapeutic strategies to treat FXS that are tailored to particular developmental stages.

Justin Fallon, PhD, Brown University, FRAXA research grant

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