Synaptogenic activity of the axon guidance molecule Robo2 underlies hippocampal circuit function

Blockus, Heike; Rolotti, Sebi V.; Szoboszlay, Miklos; Peze‐Heidsieck, Eugenie; Ming, Tiffany; Schroeder, Anna; Apóstolo, Nuno; Vennekens, Kristel M.; Katsamba, Phinikoula S.; Bahna, Fabiana; Mannepalli, Seetha; Ahlsén, Göran; Honig, Barry; Shapiro, Lawrence; Wit, Joris de; Losonczy, Attila; Polleux, Franck

doi:10.1016/j.celrep.2021.109828

Cited by 26 publications

(25 citation statements)

References 76 publications

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“…5a–c ) or dendritic spine density (Fig. 5a, d ), strongly suggesting that the signaling pathway we have identified is a bona fide stress-response pathway in dendrites upon Aβ42o exposure, as we have previously hypothesized 54 , 55 . Altogether, these results suggest a causal relationship between Aβ42o-induced MFF-dependent dendritic mitochondrial fission and dendritic spine loss.…”

Section: Resultssupporting

confidence: 72%

“…We wanted to extend this observation in vivo and for CA1 PNs. To achieve this, we performed hippocampal in utero electroporation targeting specifically CA1 PNs in wild-type or J20 (APP Swe, Ind ) mouse littermates 55 with plasmids expressing a mitochondrial matrix marker (mito-YFP), a cell filler (tdTomato), and either a control shRNA or an shRNA knocking down MFF 14 (Fig. 6a ).…”

Section: Resultsmentioning

confidence: 99%

“…In utero electroporation targeting the hippocampus was performed as previously described 2 , 116 , 117 with slight modifications as described in refs. 55 , 118 to target the embryonic hippocampus at E15.5. See Supplemental Experimental Procedures for more details.…”

Section: Methodsmentioning

confidence: 99%

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Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

et al. 2022

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During the early stages of Alzheimer’s disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β 1–42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble amyloid plaques. In a transgenic AD mouse model, we observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites corresponding to the dendritic domain where the earliest synaptic loss is detected in vivo. We also observed AMPK over-activation as well as increased fragmentation and loss of mitochondrial biomass in Ngn2-induced neurons derived from a new APPSwe/Swe knockin human ES cell line. We demonstrate that Aβ42o-dependent over-activation of the CAMKK2-AMPK kinase dyad mediates synaptic loss through coordinated phosphorylation of MFF-dependent mitochondrial fission and ULK2-dependent mitophagy. Our results uncover a unifying stress-response pathway causally linking Aβ42o-dependent structural remodeling of dendritic mitochondria to synaptic loss.

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Section: Resultssupporting

confidence: 72%

Section: Resultsmentioning

confidence: 99%

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Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

et al. 2022

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“…To understand if Lphn2 is topographically downregulated, CA1 SLM was microdissected from Pde1c-Cre -/-;DTA and Pde1c-Cre +/-;DTA groups at P15 and P30. Total RNA was extracted from the tissue and qRT-PCR analysis was performed targeting genes specific for CA1 synapses (Lphn2, (Donohue et al, 2021) Robo2 (Blockus et al, 2021) or CA3 synapses (Igsf8, Neo1 (Apóstolo et al, 2020)) to assess specificity of changes (Figure 4A). qRT-PCR analysis revealed that Lphn2 and Robo2 were both significantly upregulated at P15 Pde1c-Cre +/-;DTA compared to Pde1c-Cre -/-;DTA and conversely, were significantly downregulated at P30 Pde1c-Cre -/-;DTA compared to Pde1c-Cre -/-;DTA (Figure 4B).…”

Section: Slm Specific Effect Of Cr-cells Ablationmentioning

confidence: 99%

Persistence of Cajal-Retzius cells in the postnatal hippocampus is required for development of dendritic spines of CA1 pyramidal cells

Glærum

Dunville

Montaldo

et al. 2022

Preprint

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SummaryCajal-Retzius (CR) cells are a transient type of neuron that populate the postnatal hippocampus. The role of transient cell types and circuits have been vastly addressed in neocortical regions, but poorly studied in the hippocampus. To understand how CR cells’ persistence influences the maturation of hippocampal circuits, we specifically ablated CR cells from the postnatal hippocampus. Our results highlighted layer-specific effects on dendritic spines and synaptic-related genes and revealed a critical role of CR cells in the establishment of the hippocampal network.

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“…Recent evidence identified Neurexin (Nrxn), a co-receptor with Robo, as an essential member of a Slit-Robo-Nrxn complex that controls excitatory synapse formation in the developing hypothalamus. Specifically, presynaptic Nrxn interacts with postsynaptic Robo ( 23 ). All three Nrxn family members show expression in the fetal mouse pancreatic mesenchyme at E15.5 ( 24 ), providing substrates for potential mesenchymal Nrxn-endocrine Robo crosstalk in islet formation.…”

Section: Axon Guidance Molecules In Islet Morphogenesismentioning

confidence: 99%

Axon Guidance Molecules in the Islets of Langerhans

Waters

Blum

2022

Front. Endocrinol.

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The islets of Langerhans, responsible for regulating blood glucose in vertebrates, are clusters of endocrine cells distributed throughout the exocrine pancreas. The spatial architecture of the different cell types within the islets controls cell-cell communication and impacts their ability to collectively regulate glucose. Islets rely on a range of chemotactic and adhesive cues to establish and manage intercellular relationships. Growing evidence indicates that axon guidance molecules such as Slit-Robo, Semaphorin-Neuropilin, Ephrin-Eph, and Netrins, influence endocrine progenitors’ cell migration to establish correct architecture during islet morphogenesis, as well as directly regulating physical cell-cell communication in the mature islet to coordinate hormone secretion. In this mini-review, we discuss what is known and not yet known about how axon guidance molecules contribute to islet morphogenesis and function.

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Synaptogenic activity of the axon guidance molecule Robo2 underlies hippocampal circuit function

Cited by 26 publications

References 76 publications

Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

Persistence of Cajal-Retzius cells in the postnatal hippocampus is required for development of dendritic spines of CA1 pyramidal cells

Axon Guidance Molecules in the Islets of Langerhans

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