Neurons Generated by Mouse ESCs with Hippocampal or Cortical Identity Display Distinct Projection Patterns When Co-transplanted in the Adult Brain

Terrigno, Marco; Busti, Irene; Alia, Claudia; Pietrasanta, Marta; Arisi, Ivan; D’Onofrio, Mara; Caleo, Matteo; Cremisi, Federico

doi:10.1016/j.stemcr.2018.01.010

Cited by 18 publications

(14 citation statements)

References 64 publications

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“…This revealed that although VMpatterned cells grafted to the nigra were able to recapitulate the endogenous mesencephalic dopaminergic pathway and innervate appropriate A9 (dlSTR) and A10 (NAcc and PFC) FB target structures, FB-patterned neurons did not elicit innervation toward the dlSTR and instead preferentially innervated host cortical and limbic structures. These results point to cell-intrinsic factors determining the fiber outgrowth patterns of transplanted hESC-derived neurons and reinforce the importance of the correct patterning of grafted neurons to achieve sufficient innervation of appropriate host target structures (Espuny-Camacho et al, 2018;Gaillard et al, 2009;Hargus et al, 2010;Isacson and Deacon, 1996;Michelsen et al, 2015;Terrigno et al, 2018).…”

Section: Discussionsupporting

confidence: 53%

hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson’s Disease

et al. 2019

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Graphical AbstractHighlights d Pattern of graft-derived innervation is determined by phenotype of grafted cells d Synaptic inputs from host-to-graft depend on location of graft d Intrastriatal dopaminergic grafts receive correct excitatory and inhibitory host inputs d Individual host neurons provide inputs to both dopaminergic grafts and the host nigra SUMMARY Cell replacement is currently being explored as a therapeutic approach for neurodegenerative disease. Using stem cells as a source, transplantable progenitors can now be generated under conditions compliant with clinical application in patients. In this study, we elucidate factors controlling target-appropriate innervation and circuitry integration of human embryonic stem cell (hESC)-derived grafts after transplantation to the adult brain. We show that cell-intrinsic factors determine graft-derived axonal innervation, whereas synaptic inputs from host neurons primarily reflect the graft location. Furthermore, we provide evidence that hESC-derived dopaminergic grafts transplanted in a long-term preclinical rat model of Parkinson's disease (PD) receive synaptic input from subtypes of host cortical, striatal, and pallidal neurons that are known to regulate the function of endogenous nigral dopamine neurons. This refined understanding of how graft neurons integrate with host circuitry will be important for the design of clinical stem-cell-based replacement therapies for PD, as well as for other neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 53%

hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson’s Disease

et al. 2019

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“…Neural cells with a global gene expression profile resembling naive embryonic cortical cells can be generated by inhibiting BMP and WNT signaling pathways, which are endogenously active during mouse ESC neuralization ( Bertacchi et al., 2013 , Bertacchi et al., 2015 ). Notably, after in vivo transplantation, these cells exhibit a pattern of connectivity resembling that of their physiological counterparts, suggesting that in vitro produced cortical neurons can acquire genuine positional identities ( Terrigno et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

The microRNA miR-21 Is a Mediator of FGF8 Action on Cortical COUP-TFI Translation

et al. 2018

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SummaryThe morphogen FGF8 plays a pivotal role in neocortical area patterning through its inhibitory effect on COUP-TFI/Nr2f1 anterior expression, but its mechanism of action is poorly understood. We established an in vitro model of mouse embryonic stem cell corticogenesis in which COUP-TFI protein expression is inhibited by the activation of FGF8 in a time window corresponding to cortical area patterning. Interestingly, overexpression of the COUP-TFI 3′UTR reduces the inhibitory effect of FGF8 on COUP-TFI translation. FGF8 induces the expression of few miRNAs targeting COUP-TFI 3′UTR in silico. We found that the functional inhibition of miR-21 can effectively counteract the inhibitory effect of FGF8 in vitro and regulate COUP-TFI protein levels in vivo. Accordingly, miR-21 expression is complementary to COUP-TFI expression during corticogenesis. These data support a translational control of COUP-TFI gradient expression by FGF8 via miR-21 and contribute to our understanding of how regionalized expression is established during neocortical area mapping.

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“…Mouse ES cell corticalization in vitro, cell transfection and analysis were performed as previously described (Terrigno et al, 2018a(Terrigno et al, , 2018b. Human hiPS cells (ATCC-DYS0100 line, American Type Culture Collection) were neuralized according to Chambers at al.…”

Section: Methodsmentioning

confidence: 99%

An Eutherian-Specific microRNA Controls the Translation ofSatb2in a Model of Cortical Differentiation

Martins

Galfrè

Terrigno

et al. 2020

Preprint

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Cerebral cortical development is controlled by key transcription factors that specify the neuronal identities in the different cortical layers. These transcription factors are crucial for the identity of the different neurons, but the mechanisms controlling their expression in distinct cells are only partially known. Here we investigate the expression and stability of the mRNAs of Tbr1, Bcl11b, Fezf2, Satb2 and Cux1 in single developing mouse cortical cells. We focus on Satb2 and find that its mRNA expression occurs much earlier than its protein synthesis and in a set of cells broader than expected, suggesting an initially tight control of its translation, which is subsequently de-repressed at late developmental stages. Mechanistically, Satb2 3'UTR modulates protein translation of GFP reporters during mouse corticogenesis. By in vitro pull-down of Satb2 3'UTR-associated miRNAs, we select putative miRNAs responsible for SATB2 inhibition, focusing on those strongly expressed in early progenitor cells and reduced in late cells. miR-541, an Eutherian-specific miRNA, and miR-92a/b are the best candidates and their inactivation triggers robust and premature SATB2 translation in both mouse and human cortical cells. Our findings indicate that RNA interference plays a major role in the timing of cortical cell identity and may be part of the toolkit involved in specifying supra-granular projection neurons.

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Neurons Generated by Mouse ESCs with Hippocampal or Cortical Identity Display Distinct Projection Patterns When Co-transplanted in the Adult Brain

Cited by 18 publications

References 64 publications

hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson’s Disease

hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson’s Disease

The microRNA miR-21 Is a Mediator of FGF8 Action on Cortical COUP-TFI Translation

An Eutherian-Specific microRNA Controls the Translation ofSatb2in a Model of Cortical Differentiation

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