Neuronal LRP4 regulates synapse formation in the developing CNS

Karakatsani, Andromachi; Marichal, Nicolás; Urban, Severino; Kalamakis, Georgios; Ghanem, Alexander; Schick, Anna; Zhang, Yina; Conzelmann, Karl‐Klaus; Rüegg, Markus A.; Berninger, Benedikt; Almodóvar, Carmen Ruiz de; Gascón, Sergio; Kröger, Stephan

doi:10.1242/dev.150110

Cited by 25 publications

(46 citation statements)

References 40 publications

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“…Lrp4, like Agrin and MuSK, is expressed in the CNS. Although the roles for Agrin and MuSK in the CNS are not well understood, several studies have demonstrated that Lrp4 has an important role in the development of CNS synapses [ 72 , 73 , 74 , 75 ]. How Lrp4 functions to control CNS development is not understood.…”

Section: Fundamental Proteins Of the Neuromuscular Synapsementioning

confidence: 99%

Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses

Burden

Huijbers

Remédio

2018

IJMS

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The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine receptors (AChRs) in the postsynaptic membrane. The enrichment of proteins in presynaptic and postsynaptic membranes ensures a rapid, robust, and reliable synaptic transmission. Over fifty years ago, classic studies of the neuromuscular synapse led to a comprehensive understanding of how a synapse looks and works, but these landmark studies did not reveal the molecular mechanisms responsible for building and maintaining a synapse. During the past two-dozen years, the critical molecular players, responsible for assembling the specialized postsynaptic membrane and regulating nerve terminal differentiation, have begun to be identified and their mechanism of action better understood. Here, we describe and discuss five of these key molecular players, paying heed to their discovery as well as describing their currently understood mechanisms of action. In addition, we discuss the important gaps that remain to better understand how these proteins act to control synaptic differentiation and maintenance.

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Section: Fundamental Proteins Of the Neuromuscular Synapsementioning

confidence: 99%

Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses

Burden

Huijbers

Remédio

2018

IJMS

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“…Knockdown of LRP4 in embryonic cortical and hippocampal neurons causes a reduction in density of primary dendrites, overexpression of LRP4 in these cultured neurons had the opposite effect inducing more but shorter primary dendrites (Karakatsani et al, 2017). Neuron-specific knockdown of LRP4 by in utero electroporation of LRP4 miRNA also resulted in neurons with fewer primary dendrites in the developing cortex and hippocampus in vivo (Karakatsani et al, 2017). Embryonic cortical neurons from Lrp4 mitt mice had fewer but longer primary dendrites and transfection of agrin compensated the dendritic branching deficits in LRP4-deficient neurons (Handara et al, 2019).…”

Section: Discussionmentioning

confidence: 92%

“…LRP4 plays a crucial role in CNS, including maintaining synapses, especially in synaptic transmission [18,19]. Studies demonstrated that in the brain glutamate release was reduced in lacking LRP4 mice.…”

Section: Discussionmentioning

confidence: 99%

“…Besides, LRP4 played a role in dendritic development and synaptogenesis in the CNS. Knockdown of LRP4 in embryonic cortical and hippocampal neurons causes a reduction in density of primary dendrites, overexpression of LRP4 in these cultured neurons had the opposite effect inducing more but shorter primary dendrites (Karakatsani et al, 2017). Neuron-specific knockdown of LRP4 by in utero electroporation of LRP4 miRNA also resulted in neurons with fewer primary dendrites in the developing cortex and hippocampus in vivo (Karakatsani et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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LRP4 LDLα Repeats of Astrocyte Enhances Dendrite Arborization of the Neuron

Yan¹,

Guo²,

Chen³

et al. 2020

Preprint

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Low-density lipoprotein receptor-related protein 4 (LRP4) is essential for inducing the neuromuscular junction formation in muscle fibers, and LRP4 plays a role of dendritic development and synaptogenesis in the central nervous system (CNS). As a member of the low-density lipoprotein receptor family, LRP4 contains an enormously large extracellular region possessing multiple LDLα repeats in the N-terminal. LRP4 only with extracellular domain acts as a similar mechanism of full-length LRP4 in muscles to stimulate acetylcholine receptor clustering. In this study, we elucidated that LDLα repeats of LRP4 maintained the body weight and survival rate. Dendritic branches of the neurons in Lrp4-null mice with LRP4 LDLα repeats residue were more than in Lrp4-null mice without residual LRP4 domain. Supplement with conditioned medium from LRP4 LDLα over expression cells, primary culture neurons achieved strong dendritic arborization ability. In addition, astrocytes with LRP4 LDLα repeats residue could promoted the dendrite arborization of neurons in primary co-cultured system. These observations signify that LRP4 LDLα repeats play an underlying prominent role in dendrite arborization.

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“…As the cells grow in a flattened manner, there is not much information lost in the z -axis if the purpose is to score for a marker expressed all over the cell. However, if one wishes to adapt this protocol to study sub-cellular features such as dendritic morphogenesis or synaptogenesis, 6 , 7 these are best assessed in confocal images that provide the resolution needed for detailed sub-cellular or structural analysis.…”

Section: Anticipated Resultsmentioning

confidence: 99%

An Efficient System for Gene Perturbation in Embryonic Hippocampal Progenitors Using Ex Vivo Electroporation Followed by In Vitro Dissociated Cell Culture

2018

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We established an efficient cell culture assay that permits combinatorial genetic perturbations in hippocampal progenitors to examine cell-autonomous mechanisms of fate specification. The procedure begins with ex vivo electroporation of isolated, intact embryonic brains, in a manner similar to in utero electroporation but with greatly improved access and targeting. The electroporated region is then dissected and transiently maintained in organotypic explant culture, followed by dissociation and plating of cells on coverslips for in vitro culture. This assay recapitulates data obtained in vivo with respect to the neuron-glia cell fate switch and can be effectively used to test intrinsic or extrinsic factors that regulate this process. The advantages of this ex vivo procedure over in utero electroporation include the fact that distinct combinations of perturbative reagents can be introduced in different embryos from a single litter, and issues related to embryonic lethality of transgenic animals can be circumvented.

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Neuronal LRP4 regulates synapse formation in the developing CNS

Cited by 25 publications

References 40 publications

Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses

Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses

LRP4 LDLα Repeats of Astrocyte Enhances Dendrite Arborization of the Neuron

An Efficient System for Gene Perturbation in Embryonic Hippocampal Progenitors Using Ex Vivo Electroporation Followed by In Vitro Dissociated Cell Culture

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