Fragile X syndrome (FXS), the most common inherited form of mental retardation, result from mutations that disrupt the FMR1 gene. A large proportion of FXS patients have features of autism spectrum disorder (ASD). The protein encoded by FMR1, fragile X mental retardation protein (FMRP), binds mRNAs and regulates their translation. The identity and function of FMRP target mRNAs in human neurodevelopment and how they contribute to FXS are not well understood. In my preliminary data, parts of which formed the basis of my manuscript currently in press (Kwan et al., Cell, 2012), I show that nitric oxide synthase 1 (NOS1) mRNA is bound to and regulated by FMRP in the developing human neocortex and NOS1 protein is lost in fetal cases of FXS. Therefore, NOS1 loss of function represents a promising novel candidate mechanism of FXS. In this application, I propose to further pursue this exciting line of research.
In Aim 1, I will examine how loss of NOS1 may contribute to the pathophysiology of FXS and ASD, with which FXS is often comorbid. Specifically, I will analyze: the neurobiological role of pyramidal NOS1 during development; the genetic contribution of NOS1, and genes that act upstream of NOS1 in the synthesis of nitric oxide (NO), to ASD; and the events downstream of NOS1 signaling in pyramidal neurons.
For Aim 2, I propose to identify additional novel candidate mechanisms of FXS using postmortem human brain tissue and to test their dysregulation in FXS using FXS brains and neural stem cells. This multifaceted proposal is expected to provide training in several areas, including novel techniques in human genetics, biochemistry, human tissue processing, synapse analysis, neural stem cell culture, and high-throughput sequencing. This additional training is critical to my successful transition to independence. The progress of my training during the mentored phase and my search for an independent position will be overseen by my co-mentors and a committee of four additional faculty members with diverse expertise. The proposed studies have implications for current approaches to study of FXS and have the potential to uncover novel molecular pathways of not only FXS but also ASD.

Public Health Relevance

Fragile X syndrome is the most common inherited form of mental retardation. I propose to study the molecular underpinnings of fragile X syndrome. This work will have implications for potential therapies for fragile X syndrome, as well as autism spectrum disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Transition Award (R00)
Project #
5R00MH096939-04
Application #
8909192
Study Section
Special Emphasis Panel (NSS)
Program Officer
Anderson, Kathleen C
Project Start
2013-09-01
Project End
2016-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
4
Fiscal Year
2015
Total Cost
$248,235
Indirect Cost
$84,122
Name
University of Michigan Ann Arbor
Department
Genetics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Akins, Michael R; Berk-Rauch, Hanna E; Kwan, Kenneth Y et al. (2017) Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains. Hum Mol Genet 26:192-209
Funk, Owen H; Kwan, Kenneth Y (2014) Nitric oxide signaling in the development and evolution of language and cognitive circuits. Neurosci Res 86:77-87
Colvin, Steven M; Kwan, Kenneth Y (2014) Dysregulated nitric oxide signaling as a candidate mechanism of fragile X syndrome and other neuropsychiatric disorders. Front Genet 5:239
Kwan, Kenneth Y (2013) Transcriptional dysregulation of neocortical circuit assembly in ASD. Int Rev Neurobiol 113:167-205