Anita Bhattacharyya, PhD

Slide of the Week: Anita Bhattacharyya, PhD

Title: iPSC-Derived Forebrain Neurons from FXS Individuals Show Defects in Initial Neurite Outgrowth

Legend: Left panel: Skin cells from individuals with fragile X syndrome (FXS) can be reprogrammed into induced pluripotent stem cells (iPSCs) that have characteristics of human embryonic stem cells. These iPSCs can then be differentiated into forebrain cortical neurons to study neuronal development in FXS. Upper right panel: Neurons differentiated from FXS and control iPSCs. Control neurons express a neuron marker (red) and express fragile X mental retardation protein (FMRP, green). FXS neurons express neuron marker (red) but do not express FMRP (lack of green). Lower right panel: Human FXS neurons have decreased number and length of projections from FXS neurons as compared to control.

Citation: Doers ME, Musser MT, Nichol R, Berndt ER, Baker M, Gomez TM, Zhang SC, Abbeduto L, Bhattacharyya A. (2014) iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. Stem Cells and Development. 1;23(15):1777-87.

Abstract: Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is closely linked with autism. The genetic basis of FXS is an expansion of CGG repeats in the 5′-untranslated region of the FMR1 gene on the X chromosome leading to the loss of expression of the fragile X mental retardation protein (FMRP). The cause of FXS has been known for over 20 years, yet the full molecular and cellular consequences of this mutation remain unclear. Although mouse and fly models have provided significant understanding of this disorder and its effects on the central nervous system, insight from human studies is limited. We have created human induced pluripotent stem cell (iPSC) lines from fibroblasts obtained from individuals with FXS to enable in vitro modeling of the human disease. Three young boys with FXS who came from a well-characterized cohort representative of the range of affectedness typical for the syndrome were recruited to aid in linking cellular and behavioral phenotypes. The FMR1 mutation is preserved during the reprogramming of patient fibroblasts to iPSCs. Mosaicism of the CGG repeat length in one of the patient’s fibroblasts allowed for the generation of isogenic lines with differing CGG repeat lengths from the same patient. FXS forebrain neurons were differentiated from these iPSCs and display defective neurite initiation and extension. These cells provide a well-characterized resource to examine potential neuronal deficits caused by FXS as well as the function of FMRP in human neurons.

About the investigator: Anita Bhattacharyya’s lab examines how brain development is altered in developmental disorders characterized by intellectual impairment. The cerebral cortex is the most complex area of the brain and is responsible for functions unique to humans, such as language and abstract thought. Problems in any of the crucial cerebral cortex formation steps can lead to intellectual impairment.

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