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Lehtinen, Maria

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Lehtinen

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Maria

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Lehtinen, Maria
Author's Publications: search.filters.isAuthorOfPublication.ef257777-8ae4-4dcd-b03d-50dea90666dd

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    Downregulation of ribosome biogenesis during early forebrain development
    (eLife Sciences Publications, Ltd, 2018) Chau, Kevin F; Shannon, Morgan L; Fame, Ryann M; Fonseca, Erin; Mullan, Hillary; Johnson, Matthew B; Sendamarai, Anoop K; Springel, Mark W; Laurent, Benoit; Lehtinen, Maria
    Forebrain precursor cells are dynamic during early brain development, yet the underlying molecular changes remain elusive. We observed major differences in transcriptional signatures of precursor cells from mouse forebrain at embryonic days E8.5 vs. E10.5 (before vs. after neural tube closure). Genes encoding protein biosynthetic machinery were strongly downregulated at E10.5. This was matched by decreases in ribosome biogenesis and protein synthesis, together with age-related changes in proteomic content of the adjacent fluids. Notably, c-MYC expression and mTOR pathway signaling were also decreased at E10.5, providing potential drivers for the effects on ribosome biogenesis and protein synthesis. Interference with c-MYC at E8.5 prematurely decreased ribosome biogenesis, while persistent c-MYC expression in cortical progenitors increased transcription of protein biosynthetic machinery and enhanced ribosome biogenesis, as well as enhanced progenitor proliferation leading to subsequent macrocephaly. These findings indicate large, coordinated changes in molecular machinery of forebrain precursors during early brain development.
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    Retrograde fibroblast growth factor 22 (FGF22) signaling regulates insulin-like growth factor 2 (IGF2) expression for activity-dependent synapse stabilization in the mammalian brain
    (eLife Sciences Publications, Ltd, 2016) Terauchi, Akiko; Johnson-Venkatesh, Erin M; Bullock, Brenna; Lehtinen, Maria; Umemori, Hisashi
    Communication between pre- and postsynaptic cells promotes the initial organization of synaptic specializations, but subsequent synaptic stabilization requires transcriptional regulation. Here we show that fibroblast growth factor 22 (FGF22), a target-derived presynaptic organizer in the mouse hippocampus, induces the expression of insulin-like growth factor 2 (IGF2) for the stabilization of presynaptic terminals. FGF22 is released from CA3 pyramidal neurons and organizes the differentiation of excitatory nerve terminals formed onto them. Local application of FGF22 on the axons of dentate granule cells (DGCs), which are presynaptic to CA3 pyramidal neurons, induces IGF2 in the DGCs. IGF2, in turn, localizes to DGC presynaptic terminals and stabilizes them in an activity-dependent manner. IGF2 application rescues presynaptic defects of Fgf22-/- cultures. IGF2 is dispensable for the initial presynaptic differentiation, but is required for the following presynaptic stabilization both in vitro and in vivo. These results reveal a novel feedback signal that is critical for the activity-dependent stabilization of presynaptic terminals in the mammalian hippocampus. DOI: http://dx.doi.org/10.7554/eLife.12151.001
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    Enlargement of choroid plexus in complex regional pain syndrome
    (Nature Publishing Group, 2015) Zhou, Guangyu; Hotta, Jaakko; Lehtinen, Maria; Forss, Nina; Hari, Riitta
    The choroid plexus, located in brain ventricles, has received surprisingly little attention in clinical neuroscience. In morphometric brain analysis, we serendipitously found a 21% increase in choroid plexus volume in 12 patients suffering from complex regional pain syndrome (CRPS) compared with age- and gender-matched healthy subjects. No enlargement was observed in a group of 8 patients suffering from chronic pain of other etiologies. Our findings suggest involvement of the choroid plexus in the pathogenesis of CRPS. Since the choroid plexus can mediate interaction between peripheral and brain inflammation, our findings pinpoint the choroid plexus as an important target for future research of central pain mechanisms.
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    Proliferative and Transcriptional Identity of Distinct Classes of Neural Precursors in the Mammalian Olfactory Epithelium
    (Company of Biologists, 2010) Tucker, Eric S.; Lehtinen, Maria; Maynard, Tom; Zirlinger, Mariela; Dulac, Catherine; Rawson, Nancy; Pevny, Larysa; LaMantia, Anthony-Samuel
    Neural precursors in the developing olfactory epithelium (OE) give rise to three major neuronal classes – olfactory receptor (ORNs), vomeronasal (VRNs) and gonadotropin releasing hormone (GnRH) neurons. Nevertheless, the molecular and proliferative identities of these precursors are largely unknown. We characterized two precursor classes in the olfactory epithelium (OE) shortly after it becomes a distinct tissue at midgestation in the mouse: slowly dividing self-renewing precursors that express Meis1/2 at high levels, and rapidly dividing neurogenic precursors that express high levels of Sox2 and Ascl1. Precursors expressing high levels of Meis genes primarily reside in the lateral OE, whereas precursors expressing high levels of Sox2 and Ascl1 primarily reside in the medial OE. Fgf8 maintains these expression signatures and proliferative identities. Using electroporation in the wild-type embryonic OE in vitro as well as Fgf8, Sox2 and Ascl1 mutant mice in vivo, we found that Sox2 dose and Meis1 – independent of Pbx co-factors – regulate Ascl1 expression and the transition from lateral to medial precursor state. Thus, we have identified proliferative characteristics and a dose-dependent transcriptional network that define distinct OE precursors: medial precursors that are most probably transit amplifying neurogenic progenitors for ORNs, VRNs and GnRH neurons, and lateral precursors that include multi-potent self-renewing OE neural stem cells.