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The sorting of RNA molecules to subcellular locations facilitates the activity of spatially restricted processes. We have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these transcripts contain an enrichment of G-quadruplex sequences in their 3′ UTRs, suggesting that FMRP recognizes them to promote RNA localization. We observed similar results in neurons derived from Fragile X Syndrome patients. We identified the RGG domain of FMRP as important for binding G-quadruplexes and the transport of G-quadruplex-containing transcripts. Finally, we found that the translation and localization targets of FMRP were distinct and that an FMRP mutant that is unable to bind ribosomes still promoted localization of G-quadruplex-containing messages. This suggests that these two regulatory modes of FMRP may be functionally separated. These results provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

In a society where physical activity is limited and food supply is abundant, metabolic diseases are becoming a serious epidemic. Metabolic syndrome (MetS) represents a cluster of metabolically related symptoms such as obesity, hypertension, dyslipidemia, and carbohydrate intolerance, and significantly increases type 2 diabetes mellitus risk. Insulin resistance and hyperinsulinemia are consistent characteristics of MetS, but which of these features is the initiating insult is still widely debated. Regardless, both of these conditions trigger adverse responses from the pancreatic β cell, which is responsible for producing, storing, and releasing insulin to maintain glucose homeostasis. The observation that the degree of β cell dysfunction correlates with the severity of MetS highlights the need to better understand β cell dysfunction in the development of MetS. This Review focuses on the current understanding from rodent and human studies of the progression of β cell responses during the development of MetS, as well as recent findings addressing the complexity of β cell identity and heterogeneity within the islet during disease progression. The differential responses observed in β cells together with the heterogeneity in disease phenotypes within the patient population emphasize the need to better understand the mechanisms behind β cell adaptation, identity, and dysfunction in MetS.

In a society where physical activity is limited and food supply is abundant, metabolic diseases are becoming a serious epidemic. Metabolic syndrome (MetS) represents a cluster of metabolically related symptoms such as obesity, hypertension, dyslipidemia, and carbohydrate intolerance, and significantly increases type 2 diabetes mellitus risk. Insulin resistance and hyperinsulinemia are consistent characteristics of MetS, but which of these features is the initiating insult is still widely debated. Regardless, both of these conditions trigger adverse responses from the pancreatic [beta] cell, which is responsible for producing, storing, and releasing insulin to maintain glucose homeostasis. The observation that the degree of [beta] cell dysfunction correlates with the severity of MetS highlights the need to better understand [beta] cell dysfunction in the development of MetS. This Review focuses on the current understanding from rodent and human studies of the progression of [beta] cell responses during the development of MetS, as well as recent findings addressing the complexity of [beta] cell identity and heterogeneity within the islet during disease progression. The differential responses observed in [beta] cells together with the heterogeneity in disease phenotypes within the patient population emphasize the need to better understand the mechanisms behind [beta] cell adaptation, identity, and dysfunction in MetS.

The sorting of RNA molecules to distinct subcellular locations facilitates the activity of spatially restricted processes through local protein synthesis. This process affects thousands of transcripts yet precisely how these RNAs are trafficked to their destinations remains generally unclear. Here we have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these FMRP RNA localization targets contain a large enrichment of G-quadruplex sequences, particularly in their 3′ UTRs, suggesting that FMRP recognizes these sequences to promote the localization of transcripts that contain them. Fractionation of neurons derived from human Fragile X Syndrome patients revealed a high degree of conservation in the identity of FMRP localization targets between human and mouse as well as an enrichment of G-quadruplex sequences in human FMRP RNA localization targets. Using high-throughput RNA/protein interaction assays and single-molecule RNA FISH, we identified the RGG domain of FMRP as important for both interaction with G-quadruplex RNA sequences and the neuronal transport of G-quadruplex-containing transcripts. Finally, we used ribosome footprinting to identify translational regulatory targets of FMRP. The translational regulatory targets were not enriched for G-quadruplex sequences and were largely distinct from the RNA localization targets of FMRP, indicating that the two functions can be biochemically separated and are mediated through different target recognition mechanisms. These results establish a molecular mechanism underlying FMRP-mediated neuronal RNA localization and provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

The sorting of RNA molecules to distinct subcellular locations facilitates the activity of spatially restricted processes through local protein synthesis. This process affects thousands of transcripts yet precisely how these RNAs are trafficked to their destinations remains generally unclear. Here we have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these FMRP RNA localization targets contain a large enrichment of G-quadruplex sequences, particularly in their 3′ UTRs, suggesting that FMRP recognizes these sequences to promote the localization of transcripts that contain them. Fractionation of neurons derived from human Fragile X Syndrome patients revealed a high degree of conservation in the identity of FMRP localization targets between human and mouse as well as an enrichment of G-quadruplex sequences in human FMRP RNA localization targets. Using high-throughput RNA/protein interaction assays and single-molecule RNA FISH, we identified the RGG domain of FMRP as important for both interaction with G-quadruplex RNA sequences and the neuronal transport of G-quadruplex-containing transcripts. Finally, we used ribosome footprinting to identify translational regulatory targets of FMRP. The translational regulatory targets were not enriched for G-quadruplex sequences and were largely distinct from the RNA localization targets of FMRP, indicating that the two functions can be biochemically separated and are mediated through different target recognition mechanisms. These results establish a molecular mechanism underlying FMRP-mediated neuronal RNA localization and provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

During neural development, progenitors both divide to expand the neural progenitor (NP) population and differentiate as neurons and glia. This balance of proliferation and differentiation is crucial to the proper development of the central nervous system (CNS). This balance appears to be regulated by multiple different mechanisms including apico-basal polarization by Partitioning defective proteins (Par) as well as Hedgehog signaling, which in addition to its role in dorso-ventral patterning also promotes progenitor proliferation. How both of these pathways are modulated at the end of neurogenesis remains poorly understood. Using bioinformatics we identified the polarity genes pard3 and prkci as candidate targets for microRNA-219 (miR-219). miR-219-deficient zebrafish embryos have a deficit of oligodendrocytes, the myelinating glial cells of the CNS. Because a disruption in polarity could affect the types of cell divisions that NPs undergo, thus altering the balance of cell types that arise, we hypothesized that neural precursor maintenance is regulated by modulation of polarity cues through miR-219. We found that miR-219 inhibited expression of pard3 and prkci mRNAs via target sites in the 3’ untranslated region. These data support the role of miR-219 in downregulating expression of Par polarity proteins at the end of neurogenesis. In addition, we also found that Sonic Hedgehog (Shh) signaling was significantly increased in miR-219 morphants, suggesting a role for miR-219 in regulating the levels of Shh. Using prkci mutant zebrafish embryos we found that reduction of apical Par proteins results in a reduction of Shh signaling. These data provide evidence for a new mechanism of NP regulation, in which miR-219 downregulates apical Par proteins and Shh at the end of neurogenesis.

Using a novel murine lung squamous cell cancer model (SCC) model with topical N-nitroso-tris-chloroethylurea (NTCU) application, the authors determine the extent to which airway dysplasia develops, discuss clinic-pathologic grading criteria in lesion progression, and evaluate the squamous origin of lesions through established panels of immunohistochemical markers specific for SCC. FVB/N mice, including wild-type and prostacyclin synthase overexpressors (PGIS), were given biweekly topical applications of NTCU for 32 weeks at concentrations of 4 mM, 8 mM, and 40 mM diluted with acetone. Experimental animals received either regular rodent diet, or diet infused with iloprost, an oral prostacyclin analog. Data for the PGIS overexpressors and wild-type animals receiving iloprost diet is suggestive of a chemoprotective trend in lesion development and is more pronounced in the transgenic animals. This study demonstrates that topical application of NTCU produces endobronchial pre-malignant lesions with clear squamous characteristics immunohistochemically comparable to those seen in human smokers and is a useful model in the pre-clinical evaluation of chemopreventive agents.