Neural tube closure requires the endocytic receptor Lrp2 and its functional interaction with intracellular scaffolds

ABSTRACTPathogenic mutations in the endocytic receptor LRP2 in humans are associated with severe neural tube closure defects (NTDs) such as anencephaly and spina bifida. Here, we have combined analysis of neural tube closure in mouse and in the African Clawed Frog Xenopus laevis to elucidate the etiology of Lrp2-related NTDs. Lrp2 loss of function impaired neuroepithelial morphogenesis, culminating in NTDs that impeded anterior neural plate folding and neural tube closure in both model organisms. Loss of Lrp2 severely affected apical constriction as well as proper localization of the core planar cell polarity (PCP) protein Vangl2, demonstrating a highly conserved role of the receptor in these processes, which are essential for neural tube formation. In addition, we identified a novel functional interaction of Lrp2 with the intracellular adaptor proteins Shroom3 and Gipc1 in the developing forebrain. Our data suggest that, during neurulation, motifs within the intracellular domain of Lrp2 function as a hub that orchestrates endocytic membrane removal for efficient apical constriction, as well as PCP component trafficking in a temporospatial manner.

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Neural tube closure requires the endocytic receptor Lrp2 and its functional interaction with intracellular scaffolds

10.1101/2020.07.15.205252 ◽

2020 ◽

Author(s):

Izabela Kowalczyk ◽

Chanjae Lee ◽

Elisabeth Schuster ◽

Josefine Hoeren ◽

Valentina Trivigno ◽

...

Keyword(s):

Cell Polarity ◽

Neural Tube ◽

Planar Cell Polarity ◽

Adaptor Proteins ◽

Neural Tube Closure ◽

Model Organisms ◽

Loss Of Function ◽

Functional Interaction ◽

Apical Constriction ◽

Tube Closure

AbstractRecent studies have revealed that pathogenic mutations in the endocytic receptor LRP2 in humans are associated with severe neural tube closure defects (NTDs) such as anencephaly and spina bifida. Here, we combined analysis of neural tube closure in mouse and in the African Clawed Frog Xenopus laevis to elucidate the etiology of Lrp2-related NTDs. Lrp2 loss-of-function (LOF) impaired neuroepithelial morphogenesis, culminating in NTDs that impeded anterior neural plate folding and neural tube closure in both model organisms. Loss of Lrp2 severely affected apical constriction as well as proper localization of the core planar cell polarity (PCP) protein Vangl2, demonstrating a highly conserved role of the receptor in these processes essential for neural tube formation. In addition, we identified a novel functional interaction of Lrp2 with the intracellular adaptor proteins Shroom3 and Gipc1 in the developing forebrain. Our data suggest that during neurulation, motifs within the intracellular domain of Lrp2 function as a hub that orchestrates endocytic membrane removal for efficient apical constriction as well as PCP component trafficking in a temporospatial manner.Summary statementAnalysis of neurulation in mouse and Xenopus reveals novel roles for Lrp2-mediated endocytosis in orchestrating apical constriction and planar cell polarity essential for neural tube closure.

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Distinct spatiotemporal contribution of morphogenetic events and mechanical tissue coupling during Xenopus neural tube closure

10.1101/2021.06.01.446407 ◽

2021 ◽

Author(s):

Neophytos Christodoulou ◽

Paris Alexander Skourides

Keyword(s):

Neural Tube ◽

Cell Tracking ◽

Neural Tube Closure ◽

Convergent Extension ◽

Loss Of Function ◽

Surface Ectoderm ◽

Apical Constriction ◽

The Central Nervous System ◽

Resistive Forces ◽

Tube Closure

Neural tube closure (NTC) is a fundamental process during vertebrate embryonic development and is indispensable for the formation of the central nervous system. Here, using Xenopus laevis embryos, live imaging, single-cell tracking, optogenetics, and loss of function experiments we examine the contribution of convergent extension (CE) and apical constriction (AC) and we define the role of the surface ectoderm (SE) during NTC. We show that NTC is a two-stage process and that CE and AC do not overlap temporally while their spatial activity is distinct. PCP-driven CE is restricted to the caudal part of the neural plate (NP) and takes place during the first stage. CE is essential for correct positioning of the NP rostral most region in the midline of the dorsoventral axis. AC occurs after CE throughout the NP and is the sole contributor of anterior NTC. We go on to show that the SE is mechanically coupled with the NP providing resistive forces during NTC. Its movement towards the midline is passive and driven by forces generated through NP morphogenesis. Last, we show that increase of SE resistive forces is detrimental for NP morphogenesis, showing that correct SE development is permissive for NTC.

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Faculty Opinions recommendation of Role of Rab11 in planar cell polarity and apical constriction during vertebrate neural tube closure.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718384697.793495664 ◽

2014 ◽

Author(s):

Ira Daar

Keyword(s):

Cell Polarity ◽

Neural Tube ◽

Planar Cell Polarity ◽

Neural Tube Closure ◽

Apical Constriction ◽

Tube Closure

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A loss-of-function NUAK2 mutation in humans causes anencephaly due to impaired Hippo-YAP signaling

Journal of Experimental Medicine ◽

10.1084/jem.20191561 ◽

2020 ◽

Vol 217 (12) ◽

Author(s):

Carine Bonnard ◽

Naveenan Navaratnam ◽

Kakaly Ghosh ◽

Puck Wee Chan ◽

Thong Teck Tan ◽

...

Keyword(s):

Neural Tube ◽

Neural Progenitor Cells ◽

Neural Tube Closure ◽

Hippo Signaling ◽

Loss Of Function ◽

Serine Threonine Kinase ◽

Apical Constriction ◽

Signaling Axis ◽

Tube Closure

Failure of neural tube closure during embryonic development can result in anencephaly, one of the most common birth defects in humans. A family with recurrent anencephalic fetuses was investigated to understand its etiology and pathogenesis. Exome sequencing revealed a recessive germline 21-bp in-frame deletion in NUAK2 segregating with the disease. In vitro kinase assays demonstrated that the 7–amino acid truncation in NUAK2, a serine/threonine kinase, completely abrogated its catalytic activity. Patient-derived disease models including neural progenitor cells and cerebral organoids showed that loss of NUAK2 activity led to decreased Hippo signaling via cytoplasmic YAP retention. In neural tube–like structures, endogenous NUAK2 colocalized apically with the actomyosin network, which was disrupted in patient cells, causing impaired nucleokinesis and apical constriction. Our results establish NUAK2 as an indispensable kinase for brain development in humans and suggest that a NUAK2-Hippo signaling axis regulates cytoskeletal processes that govern cell shape during neural tube closure.

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