Regulatory discrimination of mRNAs by FMRP controls mouse adult neural stem cell differentiation

Abstract

Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), an RNA binding protein whose deficiency impacts many brain functions, including differentiation of adult neural stem cells (aNSCs). However, the mechanism by which FMRP influences these processes remains unclear. Here, we performed ribosome profiling and transcriptomic analysis of aNSCs in parallel from wild-type and Fmr1 knockout mice. Our data revealed diverse gene expression changes at both mRNA and translation levels. Many mitosis and neurogenesis genes were dysregulated primarily at the mRNA level, while numerous synaptic genes were mostly dysregulated at the translation level. Translational “buffering”, whereby changes in ribosome association with mRNA are compensated by alterations in RNA abundance, was also evident. Knockdown of NECDIN, an FMRP-repressed transcriptional factor, rescued neuronal differentiation. In addition, we discovered that FMRP regulates mitochondrial mRNA expression and energy homeostasis. Thus, FMRP controls diverse transcriptional and posttranscriptional gene expression programs critical for neural differentiation.

Ribosome and Translational Control in Stem Cells

“…Finally, FMRP (Fragile X Mental Retardation Protein), the loss of which is responsible for Fragile X syndromes, was shown to alter adult murine NSC differentiation capacities [97], mouse cognitive capacities [98], and human ESC neuronal differentiation [99]. Expression and ribosome profiling assays in murine wild type and Fmr1 KO NSCs revealed that loss of FRMP impairs both mRNA expression and translation of several neurogenesis and synaptic genes, and reduces the expression of 17 mitochondrial RP genes [100]. Interestingly, the drosophila FRMP represses translation by directly interacting with the 60S ribosomal subunit through RPL5 [101].…”

Global ribosome profiling reveals that mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein

“…As has been described before (33), several relationships between RPF and mRNA can be deciphered using ribosome profiling data. Because ribosomes are stalled in HD cells ( Fig.…”

Identification of FMRP target genes expressed in corticogenesis: implication for common phenotypes among neurodevelopmental disorders

“…Functions of FMRP have been reported to include regulation of translation, transport, and stability (De Rubeis and Bagni, 2010;Darnell et al, 2011;Ascano et al, 2012;La Fata et al, 2014;Pilaz et al, 2016;Liu et al, 2018). Although mechanisms are not fully elucidated at molecular and cellular levels, several FMRP mRNA targets are linked to various neurobiological processes such as neuronal migration and circuitry formation (La Fata et al, 2014), synaptogenesis (Darnell et al, 2011), DNA damage response (Alpatov et al, 2014), and epigenetic regulation (Korb et al, 2017).…”

“…In our study, we analyzed expression of ASD-related FMRP mRNA targets in the cortical primordium of Fmr1-KO by RT-qPCR. Only few studies have previously examined FMRP regulation on its targets at the mRNA level (Brown et al, 2001;Korb et al, 2017;Liu et al, 2018). These reports do not directly demonstrate the mechanistic role of FMRP on the transcription of its target genes, but they provide clues that mRNA levels are altered if FMRP function is impaired.…”