Behavioral and Neuroanatomical Abnormalities in Pleiotrophin Knockout Mice

Krellman, Jason W.; Ruiz, Henry H.; Marciano, Veronica A.; Mondrow, Bracha; Croll, Susan D.

doi:10.1371/journal.pone.0100597

Cited by 14 publications

(14 citation statements)

References 64 publications

(86 reference statements)

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“…PTN infusion did not influence, however, cerebrovascular dysfunction in pericyte-ablated mice as indicated by no changes in pericyte loss, CBF loss or BBB breakdown (Supplementary Fig. 9a–l) consistent with data in PTN knockout mice showing no effect on brain vasculature 40 . To determine whether PTN loss alone can trigger neuron loss in mice with intact pericyte coverage and normal circulatory function, we genetically knocked-down Ptn by small interfering RNA (si Ptn ) in TAM-treated pericyte CreER; iDTR mice.…”

Section: Resultssupporting

confidence: 87%

“…In all models, the neuroprotective effects of pericyte-conditioned media were abolished by PTN-neutralizing antibody, but not non-immune IgG (Supplementary Fig. 8f–k), consistent with PTN’s neuroprotective effects 40–42 . Moreover, restoring PTN loss in pericyte-ablated mice by reinstating physiological CSF PTN levels by a continuous intracerebroventricular infusion of a recombinant mouse PTN from day 6 of DT treatment (when pericyte loss begins) until 15 days post-DT completely prevented neuron loss and behavior deficits, in contrast to control infusion with artificial CSF (Fig.…”

Section: Resultssupporting

confidence: 70%

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Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss

et al. 2019

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Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here, we generated an inducible pericyte-specific Cre line and crossed pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor (DTR). After pericyte ablation with diphtheria toxin, mice developed an acute blood-brain barrier (BBB) breakdown, severe loss of blood flow, and a rapid neuron loss associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade linking pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings could have implications for the pathogenesis and treatment of neurological disorders associated with pericyte loss and/or neurovascular dysfunction.

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Section: Resultssupporting

confidence: 87%

Section: Resultssupporting

confidence: 70%

Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss

et al. 2019

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“…In prenatal human OPCs, PTN-PTPRZ signaling promotes proliferation, population expansion, and self-renewal through downstream regulation of the Wnt pathway (McClain et al, 2012). Underscoring the broad roles for pleiotrophin in neurodevelopment, pleiotrophin knockout mice exhibit aberrant cognitive behavior as well as anomalies in corticogenesis (Hienola et al, 2004; Krellman et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma

Qin

Cooper

Abbott

et al. 2017

Cell

167

148

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Summary The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knockdown starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion.

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“…We detected many cognition-relative genes expressed earlier in human than mouse, including PTPRZ1, CNR1, PTN , and CLSTN2 (Fig. 4A, 5A, B, C, S5A, B), that enriched in cognition, learning and memory and behavior pathways [45, 63, 76] (Fig. 5E, S5F), therefore understanding human cognition development is probably earlier than those of mouse.…”

Section: Discussionmentioning

confidence: 91%

Single-cell transcriptomic analysis identifies neocortical developmental differences between human and mouse

Zhou

Wang

Zhang

et al. 2020

Preprint

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20Background: The specification and differentiation of neocortical projection neurons is a 21complex process under precise molecular regulation; however, little is known about the 22 similarities and differences in cerebral cortex development between human and mouse at 23 single-cell resolution. 24Results: Here, using single-cell RNA-seq (scRNA-seq) data we explore the divergence 25 and conservation of human and mouse cerebral cortex development using 18,446 and 26 7,610 neocortical cells. Systematic cross-species comparison reveals that the overall 27 transcriptome profile in human cerebral cortex is similar to that in mouse such as cell types 28 and their markers genes. By single-cell trajectories analysis we find human and mouse 29 excitatory neurons have different developmental trajectories of neocortical projection 30 neurons, ligand-receptor interactions and gene expression patterns. Further analysis 31 reveals a refinement of neuron differentiation that occurred in human but not in mouse, 32suggesting that excitatory neurons in human undergo refined transcriptional states in later 33 development stage. By contrast, for glial cells and inhibitory neurons we detected 34 conserved developmental trajectories in human and mouse. 35 Conclusions: Taken together, our study integrates scRNA-seq data of cerebral cortex 36 development in human and mouse, and uncovers distinct developing models in 37 neocortical projection neurons. The earlier activation of cognition -related genes in human 38 may explain the differences in behavior, learning or memory abilities between the two 39 species. 40 41 Cognition 44 45 46 3 Background 47The mammalian cerebral cortex develops via a complex process of cell proliferation, 48 differentiation, and migration events. The molecular features of the human brain at 49 gestational weeks 7-23 are similar to those of the mouse at postnatal days 14.5 to birth 50 (P0) and reveal gene expression differences between the two species [1, 2]. Interneurons 51 and projection neurons, which are the two major classes of neurons, populate the 52 neocortex. Interneurons show largely GABAergic, connecting locally within the neocortex, 53 and are generated by progenitors in the ventral telencephalic (inhibitory cortical 54 interneuron producing) radial glia, before migrating from sub pallial ganglionic eminences 55 into the cortex [3][4][5][6]. By contrast, projection neurons are excitatory, which are generated 56 by progenitors in the dorsal telencephalic (excitatory cortical neuron producing) radial glia 57 [7][8][9]. 58 59Despite immense efforts over the past decades to study the cell types, function, 60 differentiation for the mammalian cerebral cortex, especially human and mouse, large 61 differences and conservation are observed in human versus animal models [10][11][12]. 62Elucidating the conserved, divergent and cellular architecture of developing the cerebral 63 cortex, especially projection neurons developments, may highlight to understanding 64 susceptibility to neurological diseases and the o...

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Behavioral and Neuroanatomical Abnormalities in Pleiotrophin Knockout Mice

Cited by 14 publications

References 64 publications

Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss

Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss

Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma

Single-cell transcriptomic analysis identifies neocortical developmental differences between human and mouse

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