A novel fragile X syndrome mutation reveals a conserved role for the carboxy‐terminus in
            FMRP
            localization and function

Abnormal neuronal development in Fragile X syndrome (FXS) is poorly understood. Data on FXS patients remain scarce and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons. Here, we co-injected neural precursor cells (NPCs) from FXS patient-derived and corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice. The transplanted cells populated the brain and a proportion differentiated into neurons and glial cells. Single-cell RNA sequencing of transplanted cells revealed upregulated excitatory synaptic transmission and neuronal differentiation pathways in FXS neurons. Immunofluorescence analyses showed accelerated maturation of FXS neurons after an initial delay. Additionally, increased percentages of Arc- and Egr1-positive FXS neurons and wider dendritic protrusions of mature FXS striatal medium spiny neurons pointed to an increase in synaptic activity and synaptic strength as compared to control. This transplantation approach provides new insights into the alterations of neuronal development in FXS by facilitating physiological development of cells in a 3D context, and could be used to test new therapeutic compounds correcting neuronal development defects in FXS.

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The behavioral neurogenetics of fragile X syndrome: Analyzing gene–brain–behavior relationships in child developmental psychopathologies

Development and Psychopathology ◽

10.1017/s0954579403000464 ◽

2003 ◽

Vol 15 (4) ◽

pp. 927-968 ◽

Cited By ~ 89

Author(s):

ALLAN L. REISS ◽

CHRISTOPHER C. DANT

Keyword(s):

Environmental Factors ◽

Fragile X Syndrome ◽

Neurodevelopmental Disorders ◽

Fragile X ◽

Single Gene ◽

Structure And Function ◽

Research Approach ◽

And Function ◽

And Behavior ◽

Brain Behavior

Analyzing gene–brain–behavior linkages in childhood neurodevelopmental disorders, a research approach called “behavioral neurogenetics,” has provided new insights into understanding how both genetic and environmental factors contribute to complex variations in typical and atypical human development. Research into etiologically more homogeneous disorders, such as fragile X syndrome, in particular, allows the use of more precise metrics of genetic risk so that we can more fully understand the complex pathophysiology of childhood onset neurodevelopmental disorders. In this paper, we review our laboratory's behavioral neurogenetics research by examining gene–brain–behavior relationships in fragile X syndrome, a single-gene disorder that has become a well-characterized model for studying neurodevelopmental dysfunction in childhood. Specifically, we examine genetic influences, trajectories of cognition and behavior, variation in brain structure and function, and biological and environmental factors that influence developmental and cognitive outcomes of children with fragile X. The converging approaches across these multilevel scientific domains indicate that fragile X, which arises from disruption of a single gene leading to the loss of a specific protein, is associated with a cascade of aberrations in neurodevelopment, resulting in a central nervous system that is suboptimal with respect to structure and function. In turn, structural and functional brain alterations lead to early disruption in emotion, cognition, and behavior in the child with fragile X. The combination of molecular genetics, neuroimaging, and behavioral research have advanced our understanding of the linkages between genetic variables, neurobiological measures, IQ, and behavior. Our research and that of others demonstrates that neurobehavior and neurocognition, genetics, and neuroanatomy are all different views of the same intriguing biological puzzle, a puzzle that today is rapidly emerging into a more complete picture of the intricate linkages among gene, brain, and behavior in developing children. Understanding the complex multilevel scientific perspective involved in fragile X will also contribute to our understanding of normal development by highlighting developmental events throughout the life span, thereby helping us to delineate the boundaries of pathology.

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Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

10.21203/rs.3.rs-158378/v1 ◽

2021 ◽

Author(s):

Pernille Bülow ◽

Peter A Wenner ◽

Victor Faundez ◽

Gary J Bassell

Keyword(s):

Fragile X Syndrome ◽

Neurodevelopmental Disorders ◽

Neuronal Plasticity ◽

Cortical Neurons ◽

Initial Segment ◽

Fragile X ◽

Axon Initial Segment ◽

Homeostatic Plasticity ◽

Mitochondrial Morphology ◽

And Function

Abstract Mitochondrial dysfunction has long been overlooked in neurodevelopmental disorders, but recent studies have provided new links to genetic forms of autism, including Rett syndrome and Fragile X Syndrome (FXS). In parallel, recent studies have uncovered important basic functions of mitochondria to power protein synthesis, synaptic plasticity and neuronal maturation. The mitochondrion also responds to neuronal activity by altering its morphology and function, and this plasticity of the mitochondrion appear important for proper neuronal plasticity. Previous research has reported disease induced changes in mitochondrial morphology and function, but it remains unknown how such abnormalities affect the ability of mitochondria to express activity dependent plasticity. This study addresses this gap in knowledge using a mouse model of FXS. We previously reported abnormalities in one type of homeostatic plasticity, called homeostatic intrinsic plasticity, which is known to involve structural changes in the axon initial segment (AIS). Another form of homeostatic plasticity, called synaptic scaling, which involves postsynaptic changes in dendrites, is also impaired in FXS. It remains unknown if or how homeostatic plasticity affects mitochondria in axons and/or dendrites and whether impairments occur in neurodevelopmental disorders. Here, we test the hypothesis that mitochondria are structurally and functionally modified in a compartment specific manner during homeostatic plasticity in cortical neurons from wild type mice, and that this plasticity-induced regulation is altered in Fmr1 KO neurons, as a model of FXS. We uncovered dendritic specific regulation of mitochondrial surface area, whereas AIS mitochondria show changes in polarity; both responses are lost in Fmr1 KO. Taken together our results demonstrate impairments in mitochondrial plasticity in FXS, which has not previously been reported. These results suggest that mitochondrial dysregulation in FXS contributes to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.

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Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment Are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.702020 ◽

2021 ◽

Vol 9 ◽

Author(s):

Pernille Bülow ◽

Peter A. Wenner ◽

Victor Faundez ◽

Gary J. Bassell

Keyword(s):

Fragile X Syndrome ◽

Neurodevelopmental Disorders ◽

Cortical Neurons ◽

Initial Segment ◽

Fragile X ◽

Axon Initial Segment ◽

Homeostatic Plasticity ◽

Mitochondrial Morphology ◽

Specific Regulation ◽

And Function

Mitochondrial dysfunction has long been overlooked in neurodevelopmental disorders, but recent studies have provided new links to genetic forms of autism, including Rett syndrome and fragile X syndrome (FXS). Mitochondria show plasticity in morphology and function in response to neuronal activity, and previous research has reported impairments in mitochondrial morphology and function in disease. We and others have previously reported abnormalities in distinct types of homeostatic plasticity in FXS. It remains unknown if or how activity deprivation triggering homeostatic plasticity affects mitochondria in axons and/or dendrites and whether impairments occur in neurodevelopmental disorders. Here, we test the hypothesis that mitochondria are structurally and functionally modified in a compartment-specific manner during homeostatic plasticity using a model of activity deprivation in cortical neurons from wild-type mice and that this plasticity-induced regulation is altered in Fmr1-knockout (KO) neurons. We uncovered dendrite-specific regulation of the mitochondrial surface area, whereas axon initial segment (AIS) mitochondria show changes in polarity; both responses are lost in the Fmr1 KO. Taken together, our results demonstrate impairments in mitochondrial plasticity in FXS, which has not previously been reported. These results suggest that mitochondrial dysregulation in FXS could contribute to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.

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Fragile X Syndrome: Loss of Local mRNA Regulation Alters Synaptic Development and Function

Neuron ◽

10.1016/j.neuron.2008.10.004 ◽

2008 ◽

Vol 60 (2) ◽

pp. 201-214 ◽

Cited By ~ 640

Author(s):

Gary J. Bassell ◽

Stephen T. Warren

Keyword(s):

Fragile X Syndrome ◽

Fragile X ◽

Synaptic Development ◽

Mrna Regulation ◽

And Function

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critical role of astrogenesis and neurodevelopment in Fragile X Syndrome and Rett Syndrome

McMaster University Medical Journal ◽

10.15173/mumj.v17i1.2338 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

John Paul Oliveria ◽

Zhuo Jun Li

Keyword(s):

Fragile X Syndrome ◽

Rett Syndrome ◽

Fragile X ◽

Critical Role ◽

Notch Pathway ◽

Janus Kinase ◽

Future Research ◽

Genetic Mutations ◽

And Function ◽

The Brain

Astrocytes play an important role in the development of functional neural circuits in the brain. They are responsible for coordinating synapse formation and function, axon guidance, and ensuring neuronal survival. Normal astrogenesis begins during late gestation. Neural stem cells (NSCs) become primarily gliogenic and differentiate to become astrocyte precursors. Through local proliferation and functional maturation, the precursors develop into mature astrocytes, which can either be fibrous or protoplasmic. Astrogenesis is regulated by both cell intrinsic programs and cell extrinsic cues. Intrinsic chromatin changes, such as demethylation of astrocyte-specific genes, allows the NSCs to become responsive to astrocyte-inducing exogenous cues. These cues involve a collaboration of multiple pathways, namely the Notch pathway, the bone morphogenetic protein (BMP) signaling pathway, interleukin-6 (IL-6) signaling, and the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway. Together, they allow for normal astrogenesis to occur. However, disruption to these pathways lead to abnormal astrocyte development and results in pathologies such as the Fragile X Syndrome (FXS) and Rett Syndrome (RS). Both neurodevelopmental disorders are a result of genetic mutations that causes either transcriptional silence or transcriptional activation at inappropriate stages during development. These genetic mutations result in depressed astrocyte function in FXS, and the overexcitement of astrocytes in RS. The current hypothesis under investigation is that altered gene transcription during neurodevelopment disrupts astrogenesis, and subsequently, the behavior and function of mature astrocytes in the brain. Future research should focus on understanding the timing of the transition from neurogenesis to astrogenesis and identifying astrocyte-specific markers that are critical to its function in neurodevelopment.

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Human-mouse chimeric Fragile X syndrome model reveals FMR1-dependent neuronal phenotypes

10.21203/rs.3.rs-83372/v1 ◽

2020 ◽

Author(s):

Marine Krzisch ◽

Hao Wu ◽

Bingbing Yuan ◽

Troy Whitfield ◽

Shawn Liu ◽

...

Keyword(s):

Fragile X Syndrome ◽

Neuronal Development ◽

Fragile X ◽

In Vitro Models ◽

Synaptic Activity ◽

Human Neurons ◽

Induced Pluripotent ◽

And Function ◽

The Brain

Abstract Abnormal neuronal development in Fragile X syndrome (FXS) is poorly understood. Data on FXS patients remain scarce and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons. Here, we co-injected neural precursor cells (NPCs) from FXS patient-derived and corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice. The cells populated the brain and differentiated into neurons and astrocytes. Single-cell RNA sequencing of transplanted cells revealed upregulated excitatory synaptic transmission and neuronal differentiation pathways in FXS neurons. Immunofluorescence analyses showed accelerated maturation of FXS neurons, an increased proportion of Arc-positive FXS neurons and increased dendritic protrusion width of FXS striatal medium spiny neurons. Our data show faster maturation and suggest increased synaptic activity and synaptic strength of FXS transplanted neurons. This model provides new insights into the alterations in FXS neuronal development.

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Gesture Frequency and Function in Infants With Fragile X Syndrome and Infant Siblings of Children With Autism Spectrum Disorder

Journal of Speech Language and Hearing Research ◽

10.1044/2019_jslhr-l-17-0491 ◽

2019 ◽

Vol 62 (7) ◽

pp. 2386-2399 ◽

Cited By ~ 2

Author(s):

K. R. Hughes ◽

Abigail L. Hogan ◽

Jane E. Roberts ◽

Jessica Klusek

Keyword(s):

Autism Spectrum Disorder ◽

Fragile X Syndrome ◽

Fragile X ◽

Children With Autism ◽

Communication Disorders ◽

Autism Spectrum ◽

Low Risk ◽

Spectrum Disorder ◽

Infant Siblings ◽

And Function

PurposeInfant siblings of children with autism spectrum disorder (ASIBs) and infants with fragile X syndrome (FXS) are both at risk for developing autism spectrum disorder (ASD) and communication disorders; however, very few studies have examined 1 of the earliest forms of intentional communication in infants from these groups: gestures. This study examined the frequency and function of gesture use across 12-month-old infant ASIBs, infants with FXS, and low-risk controls.MethodParticipants included 23 ASIBs who did not later meet diagnostic criteria for ASD, 18 infants with FXS, and 21 low-risk controls. Gestures were coded from a semistructured play-based interaction.ResultsOverall, infants with FXS displayed fewer gestures than low-risk infants, whereas ASIBs did not differ from the FXS or low-risk groups in overall gesture frequency. In terms of the communicative function of the gestures used, the FXS and ASIB groups displayed significantly fewer social interaction gestures than the low-risk controls, with large effect sizes.ConclusionThis study contributes to scant knowledge of early communication phenotypes of infant ASIBs who do not meet criteria for ASD and infants with FXS. Results indicated that gesture function, not frequency, best discriminated at-risk infants from low-risk infants at 12 months of age. Findings have implications for the clinical evaluation and treatment of infants at high risk for ASD and communication disorders.

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