Abstract
An increasing body of evidence indicates that astrocytes contribute to the governance and fine tuning of stem and progenitor cell production during brain development. The effect of astrocyte function in cell production in neurodevelopmental disorders is unknown. We used the Neural Colony Forming Cell assay to determine the effect of astrocyte conditioned media (ACM) on the generation of neurospheres originating from either progenitor cells or functional stem cells in the knock out (KO) Fragile X mouse model. ACM from both normal and Fmr1-KO mice generated higher percentages of smaller neurospheres indicative of restricted proliferation of the progenitor cell population in Fmr1-KO brains. Wild type (WT) neurospheres, but not KO neurospheres, showed enhanced responses to ACM from the Fmr1-KO mice. In particular, Fmr1-KO ACM increased the percentage of large neurospheres generated, representative of spheres produced from neural stem cells. We also used 2D DIGE to initiate identification of the astrocyte-secreted proteins with differential expression between Fmr1-KO and WT cortices and hippocampi. The results further support the critical role of astrocytes in governing neural cell production in brain development and point to significant alterations in neural cell proliferation due to astrocyte secreted factors from the Fragile X brain.Highlights:• We studied the proliferation of neural stem and progenitor cells in Fragile X.• We examined the role of astrocyte-secreted factors in neural precursor cell biology.• Astrocyte-secreted factors with differential expression in Fragile X identified.
Highlights
Fragile X Syndrome (FXS) is the most common single-gene cause of autism spectrum disorder and intellectual impairment (Wang et al, 2012), with a frequency of about 1 in 7,100 males and 1 in 11,100 females (Hunter et al, 2014)
We examined the proliferation of hippocampal neural progenitor and stem cells from the early postnatal Fmr1-KO mouse brain
We found that Fmr1-KO progenitorderived neurospheres showed decreased proliferation in response to WT and Fmr1-KO ACM, thereby demonstrating noncell autonomous defects in responding correctly to astrocytesecreted factors
Summary
Fragile X Syndrome (FXS) is the most common single-gene cause of autism spectrum disorder and intellectual impairment (Wang et al, 2012), with a frequency of about 1 in 7,100 males and 1 in 11,100 females (Hunter et al, 2014). Conditional knockout of FMRP in adult NPCs results in increased NPC proliferation, and the consequent impairment of hippocampus dependent learning (Guo et al, 2011). The majority of DG granule cells are born postnatally in the rodent brain (Altman and Bayer, 1990), and most adult born neurons are generated from early-born NPCs that reside in the DG as it is forming (Mathews et al, 2010). It is unknown whether early postnatal dysregulation of NPCs has ramifications on neurogenesis throughout life, or whether later interventions can correct abnormalities. Regulation of neurogenesis via FMRP is likely to impact early-born NPCs in the developing DG since expression of FMRP peaks at postnatal day 7 (Lu et al, 2004), which may underlie abnormal hippocampus-dependent memory in 3-week-old Fragile X mice (Bilousova et al, 2009)
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