Fmrp regulates oligodendrocyte lineage cell specification and differentiation

Abstract

Neurodevelopment requires the precise integration of a wide variety of neuronal and glial cell types. During early embryonic development, motor neurons and then oligodendrocyte precursor cells (OPCs) are specified from neural progenitors residing in the periventricular pMN progenitor domain of the spinal cord. Following gliogenesis, OPCs can differentiate as oligodendrocytes (OLs)—the myelinating glial cells of the central nervous system—or remain as OPCs. To generate unique cell types capable of highly divergent functions, these specification and differentiation events require specialized gene expression programs. RNA binding proteins (RBPs) regulate mRNA localization and translation in the developing nervous system and are linked to many neurodevelopmental disorders. One example is Fragile X syndrome (FXS), caused by the loss of the RBP fragile X mental retardation protein (FMRP). Importantly, infants with FXS have reduced white matter and we previously showed that zebrafish Fmrp is autonomously required in OLs to promote myelin sheath growth. We now find that Fmrp regulates cell specification in pMN progenitor cells such that fmr1 mutant zebrafish generate fewer motor neurons and excess OPCs. Fmrp subsequently promotes differentiation of OPCs, leading to fewer differentiating OLs in the developing spinal cord of fmr1 larvae. Although the early patterning of spinal progenitor domains appears largely normal in fmr1 mutants during early embryogenesis, Shh signaling is greatly diminished. Taken together, these results suggest cell stage‐specific requirements for Fmrp in the specification and differentiation of oligodendrocyte lineage cells.

Glial dysregulation in human brain in Fragile X-related disorders

“…(Figure 3 figure supplement 3). In cerebral cortex in FXS there was an increase in OPC proportion; this finding has previously been observed in animal models (Doll et al, 2021) although to our knowledge not previously described in humans. Thus, FXS and PM cases are associated with distinct alterations in the brain’s cellular architecture.…”

“…Our small sample size of Fragile X syndrome increases chances that changes in cellular proportion or transcriptional dysregulation may be due to stochastic artifacts. However, replication of past findings including reduced FMR1 expression (Pieretti et al, 1991; Bhattacharyya & Zhao, 2016), increased OPC proportion (Doll et al, 2021), and widespread evidence of metabolic stress (Donnard et al, 2020; Kang et al, 2021), corroborate known molecular neuropathology of the disorder (Licznerski et al, 2020).…”

“…However, replication of past findings including reduced FMR1 expression (Pieretti et al, 1991;Bhattacharyya & Zhao, 2016), increased OPC proportion (Doll et al, 2021), and widespread evidence of metabolic stress (Donnard et al, 2020;Kang et al, 2021), corroborate known molecular neuropathology of the disorder (Licznerski et al, 2020). Thus, our findings highlight the need for more comprehensive study of Fragile X in human tissue directly in a variety of different cell types.…”

“…It is also possible that reduced FMRP contributes to PM pathology in a developmentally distinct manner from the total loss that occurs in FXS. Finally, while studies of the impact of FMR1 disruption have been focused on post-mitotic neurons, there is increasing evidence implicating important roles for FMR1 in a diversity of cellular subtypes at multiple points in nervous system development, including in glia (Giampetruzzi et al, 2013;Martínez Cerdeño et al, 2018;Doll et al, 2020;Doll et al, 2021;Raj et al, 2021). Despite these gaps in knowledge, there has been no cell-type specific analysis of transcriptional changes related to Fragile X in human brain to date.…”

Fmrp regulates neuronal balance in embryonic motor circuit formation

“…5A), which may suggest that Fmrp also regulates VeLD positioning in the cord. Taken together with our previous INs from the pMN domain (Doll et al, 2021). + cord (Fig.…”