Kowalczyk I , Lee C , Schuster E , Hoeren J , Trivigno V , Riedel L , Görne J , Wallingford JB , Hammes A , Feistel K .

R01 GM104853 NIGMS NIH HHS , R01 HD099191 NICHD NIH HHS

             apical constriction
             forebrain development

                holoprosencephaly

Xla Wt + gipc1 MO (Fig.S5.G,G',I,J)
Xla Wt + gipc1 MO + lrp2 MO (Fig.7.F,G)
Xla Wt + lrp2 CRISPR (Fig.7.K,N)
Xla Wt + lrp2 CRISPR (Fig.S2.D)
Xla Wt + lrp2 CRISPR (Fig.S2.F)
Xla Wt + lrp2 MO (Fig,S4.H,I,K)
Xla Wt + lrp2 MO (Fig.2.I)
Xla Wt + lrp2 MO (Fig.2.J,J'')
Xla Wt + lrp2 MO (Fig.2.L,N)
Xla Wt + lrp2 MO (Fig.3.A,A1,C,E,C1,J)
Xla Wt + lrp2 MO (Fig.4.E,I,I')
Xla Wt + lrp2 MO (Fig.7.D,G)
Xla Wt + lrp2 MO (Fig.7.I,I1)
Xla Wt + lrp2 MO (Fig.S3)
Xla Wt + lrp2 MO (Movie 1)
Xla Wt + lrp2 MO (Movie 2)
Xla Wt + shroom3 MO (Fig.6.A,A1,A2)

	Fig. 1. Lrp2 is expressed in the neuroepithelium and increased in constricting cells. (A-D) lrp2 mRNA (A) and protein (B-D) expression analyzed by in situ hybridization and immunofluorescence, respectively. Neurula stage (st.) embryos (frontal views, dorsal upwards). (A) Neural lrp2 expression. (B) Stage 15 forebrain region; Lrp2 is expressed in most cells (outlined by F-actin); single cells with high Lrp2 levels are located along the anterior rim of neural folds (NFs; arrowheads). (B′) Magnification of boxed region in B; increased Lrp2 levels are found in cells with small apical surface (circled in single channels B′1 and B′2). (C) LRP2 is detected throughout E8.5 anterior NFs, concentrated in areas undergoing apical constriction. Compare C′ (constricted cells in optic evagination) with C″ (dorsolateral cells with larger cell surface). ZO-1 marks cell boundaries. (D) STED imaging; LRP2 is condensed around neuroepithelial primary cilia (ARL13b+) at E9.5. Scale bars: 10 µm in B′,C′,C″; 1 µm in D.
	Fig. 2. Lrp2 is required for proper neuroepithelial morphogenesis and neural tube closure. Neural plate (NP) morphology. (A-F) Scanning electron micrographs of neural folds (NFs) from E8.5 wild-type (WT) and Lrp2−/− mouse embryos at the 6-, 7- and 8-somite (som) stages (st.), frontal views. (A-C) Wild-type NFs are progressively elevated and optic evagination is initiated (arrowheads in B,C). (D-F) Narrower NFs have delayed elevation and there is impaired optic evagination in mutants (arrowheads in E,F). (G,H) Immunofluorescence staining detecting acetylated α-tubulin (ac. α-tub.) and DAPI-stained nuclei on coronal sections of 10-somite wild-type and Lrp2−/− mouse NFs. Scale bars: 100 µm in A-F; 50 µm in G,H. (I,J) Dotted lines indicate normal (green) and abnormal (red) positioning of the border between neural and non-neural ectoderm. (I) Morpholino oligomer targeting lrp2.L (lrp2 MO) injected as indicated. Impaired hingepoint formation and NF convergence on the injected side are indicated (asterisk). (J) Closely apposed NFs in control at stage 19. Open anterior and posterior NFs, and a short anteroposterior axis are formed upon bilateral injection (asterisks); embryos were photographed at the same magnification. (J′,J″,J′1,J″1) Transverse sections and magnifications thereof; levels are as indicated in J. Green markers indicate normal floor plate width (J′) and apical cell surfaces (J′1); red markers indicate wide floor plate (J″) and abnormally wide apical cell surfaces (J″1). (K-M) In situ hybridization for sox3; normal NP width (green bar) is found in control (K); lrp2 MO-impaired NP narrowing (red bar, L) was partially rescued (yellow bar) by re-introduction of lrp2 (M). (N) Graphical representation of results from K-M (box plot, Wilcoxon rank sum test).
	Fig. 3. Lrp2 is cell-autonomously required for efficient apical constriction. Apical constriction (AC) in forebrain neural plate (NP) cells. (A,A1) F-actin revealed a larger apical cell surface in lrp2 morpholino oligomer (MO)-injected cells (identified by lineage tracer fluorescence) compared with the uninjected side; there was a lack of AC in the optic evagination (ev.) area on the injected side. (B-E) Quantification of cell surface areas in unilaterally injected lineage tracer-only controls (B,B1), lrp2 morphants (C,C1) and morphants with re-introduced lrp2 (D,D1). (E) Cell surface area ratios calculated between injected and uninjected sides; box plot and Wilcoxon rank sum test. (F) The intermingling of constricting NP cells with lrp2 morphant cells demonstrates cell autonomy of AC failure. (G,H) Frontal views of the forebrain area of wild-type (WT; G) and Lrp2−/− (H) 7-somite stage mouse embryos at E8.5; ZO-1 delineates cell borders. (G′,H′) Magnification of optic evagination area, indicated in G,H; cell surface area was increased in mutants. (G″,H″) Color-coded maps (areas indicated in G,H) visualize cell surface area. (I) Graphical representation of results from G″,H″; four areas from each embryo were analyzed; box plot and Student's t-test. (J) Live imaging (Movie 2) using LifeAct indicates a failure of AC in morphant cells, despite actin dynamics. Cell surface area measurements revealed size fluctuations; final AC occured in control cells only. Scale bars: 25 µm in A-D,F; 20 µm in G,H.
	Fig. 4. No efficient remodeling of the apical surface in cells with apical constriction failure. (A-D) Scanning electron micrographs of mouse neuroepithelial cells at E8.5. Prominent filamentous, microvilli-like protrusions were present on wild-type (WT; A) and LRP2-deficient (Lrp2−/−; B) cells at the 7-somite (som) stage. Reduced filamentous protrusions are seen at the 9-somite stage in the wild type (C), but are persistent in Lrp2−/− (D). (E) Transverse section of Xenopus forebrain area at stage 19; lrp2 morpholino oligomer (MO)-positive cells are identified by their enlarged apical surface and by cytosolic lineage tracer fluorescence. Embryos were incubated in fluorescent dextran from stages 14 to 19. Signal is present in constricted cells (filled arrowheads) but absent from MO-targeted cells (empty arrowheads). F-actin staining indicates cell borders. (F,G) Transmission electron micrographs of E9.5 coronal ultrathin sections. Normal apical cell diameters (green lines) and moderate bulging are present in the wild type (F); increased cell diameter (red lines) and excessive bulging are found in Lrp2−/− cells (G). (H) Quantification and statistical analysis of cell diameters. Student's t-test. Data are mean±s.e.m. (I) En face view of neural plate showing apically enlarged lrp2 MO-targeted cells (lineage tracer+) bulged outwards, see orthogonal view (I′; optical section at level indicated in I). Scale bars: 2 µm in A-D; 20 µm in E; 2 µm in F,G; 10 µm in I.
	Fig. 5. Lrp2 is required for planar cell polarity and regulates subcellular localization of Vangl2. Analysis of planar cell polarity in embryos en face (A-E) and on sections (F-H). (A) Scheme for injection of morpholino oligomer (MO) targeting lrp2; area for analysis at stage (st.) 16 in B is indicated by a box. (B) Dorsal view of mid-/hindbrain area; the width of the neural plate is greater on the injected side, F-actin delineates cell borders. (B1) Bright-field image of same embryo shows pigment granule localization towards the anterior in uninjected control cells (B1′); circumferential distribution is seen in apically wide morphant cells (B1″). (C) Beginning of asymmetric Lrp2 distribution; F-actin delineates cell borders. (C′) Magnification of area indicated in C; there is medio-anterior distribution of Lrp2 (arrowheads in C′1), which is also seen in apically constricted cells (circle in C′1). (C′2) F-actin single channel. (D,E) eYFP-vangl2 injected into the A1 lineage in 4- to 8-cell embryos, detected at stage 15 using immunofluorescence for GFP and F-actin staining. Dotted pattern of eYFP-Vangl2 expression (6/6 embryos; D,D′; magnification of inset in D), which is located subapically in vesicle-like structures (green arrowheads in D″; optical section indicated in D′; magenta arrowheads indicate f-Actin belt). Upon lrp2 MO injection, Vangl2 localized at cell borders (7/9 embryos, two independent experiments; E,E′) and subapically in the basolateral membrane (green arrowheads in E″, optical section as indicated in E′; magenta arrowheads indicate f-Actin belt). (D′1,D′2,E′1,E′2) Single channels. (F) Schematic illustrating the level of transverse sections in G,H. (G,H) LRP2 and VANGL2 distribution at the 9-somite stage. (G′,G′1-3,H′,H′1-3) Higher magnifications of the areas indicated by the boxes in G,H, and single channels thereof. Apical colocalization (dashed circles) of LRP2 and VANGL2 in RAB11-positive compartments occurs in wild type (WT; G,G′) compared with absence of VANGL2 from RAB11-positive compartments in Lrp2−/− cells (H,H′); arrowheads in H′3 indicate relocalization of VANGL2 to the basolateral membrane. l, left; p, posterior; r, right; v, ventral. Scale bars: 100 µm in B; 10 µm in C′,D′,E′; 5 µm in G′,H′.
	Fig. 6. lrp2 functionally interacts with shroom3 in mediating apical constriction. (A) Transverse section through neural plate; unilateral injection of shroom3 morpholino oligomer (MO) produces a failure of apical constriction (α-tubulin highlights wide cell surfaces; A1); apical Lrp2 accumulation in constricting hinge point cells (arrowheads in A2) and lack of apical Lrp2 recruitment in targeted cells. (B) Section through animal cap; ectopic apical constriction is induced in cells injected with shroom3-myc (detected by anti-Myc antibody; B1) coinciding with apical Lrp2 accumulation (arrowheads in B2). (C-E) shroom3-induced ectopic apical constriction in animal cap cells at stage (st.) 10.5 (C) is abrogated by co-injection of lrp2 MO (D) and restored by co-injection of lrp2. (F) Quantification and statistical analysis of experiments in C-E: no, mild or strong ectopic constriction are quantified. N=number of experiments; n=number of embryos, χ2 test.
	Fig. 7. Lrp2 mediates apical constriction by functional interaction with Gipc1. (A) Frontal view of wild-type (WT) mouse forebrain area at E8.5 (7 somites). Immunofluorescence (IF) staining reveals localization of GIPC1 and LRP2; ZO-1 marks cell borders. (A1-A3) Single channels. (A1′-A3″) Magnification of areas indicated in A1-A3; differential GIPC1 intensities exist between large and constricted cells. (B,C) Frontal views of stage (st.) 16 (B) and stage 15 (C) embryos; dashed line indicates the anterior limit of the neural plate; immunofluorescence reveals the spatially dynamic localization of Gipc1 (B) and spatially dynamic colocalization of Lrp2 and Gipc1 (C). (B′) Single channel of Gipc1; higher magnification of the area indicated in B. Boxed areas indicated in C are shown at higher magnification in C′-C″″. (C′1,C″1,C′2,C″2) Single channels. Gipc1 is present in areas with low (C′1,C′2) or high (C″1,C″2) amounts of Lrp2. Dispersed distribution of Lrp2 and Gipc1 in a cell with a large apical surface (C″′), also visible in an orthogonal optical section (C‴a; indicated in C‴); sites of Lrp2/Gipc1 co-localization are indicated (white arrowheads). (C″″) Cell with a constricted surface showing Gipc1 accumulation. (C⁗a,C⁗b) Colocalization (white arrowheads) or separate localization (green or magenta arrowheads) are indicated. Blue arrowheads indicate the level of circumferential actin; dashed line indicates apical surface in C″′a,C⁗a,C⁗b. (D-F) Functional interaction of Lrp2 and Gipc1 demonstrated by individual (D,E) or combined (F) injection of low-dose lrp2/gipc1 morpholino oligomer (MO); targeted cells with lineage tracer (LT) fluorescence are shown. (G) Graphical representation of results from D-F; box plot and Wilcoxon rank sum test. (H) Frontal view of LRP2-deficient (Lrp2−/−) mouse forebrain area at E8.5 (seven somites). Immunofluorescence reveals localization of Gipc1; ZO-1 outlines cells. (H1,H2) Single channels. There is homogenous GIPC1 signal throughout the neuroepithelium. (I) Mislocalization of Gipc1 in lrp2 MO-injected cells in stage 16 embryos; the magnified forebrain area is marked by a box in the schematic. Targeted cells are identified by LT; dashed line delineates targeted/non-targeted areas. (I1) Without LT. (I1′,I1″) Higher magnification of single cells indicated by the boxes in I1; Gipc1 increases in hindbrain and decreases in the forebrain area. (J-M) Embryos for CRISPR/Cas9 experiments selected at the one-cell stage and incubated until uninjected controls (J) reached stage 18/19. (K) Injection of Cas9 ribonucleic particles (CRNP) containing sgRNA1. (L,M) Co-injection of CRNP together with the lrp2 construct (L) or with lrp2 ΔPBD (M). (N) Graphical representation of results from J-M, χ2 test. Cell borders in D-F,I are visualized using F-actin staining. Scale bars: 50 µm in A,C,H,I; 100 µm in B; 20 µm in D-F.
	Fig. 8. Hypothetical model of Lrp2 functional interactions in neural tube closure. Apical constriction is seen as a stepwise process with repetitive modules of actomyosin-mediated constriction and Lrp2-mediated membrane removal (left column). Apical constriction of Lrp2-positive neuroepithelial cells facilitates neural tube closure (middle column). Lrp2 mediates endocytic removal of apical membrane (1) as well as correct temporospatial localization of Vangl2 (2) via recycling endosomes. The Lrp2/Vangl2 interaction is likely facilitated by PDZ/PBD-mediated intracellular scaffolding via dimerized Gipc1, connecting to Myo6 and the actin cytoskeleton. Lack of Lrp2 (right column) entails defective neural tube closure due to impaired apical constriction. Removal of apical membrane fails and proper subcellular sorting of Vangl2 and Gipc1 is disturbed, leading to their mislocalization.
	Fig. S1: Lrp2 expression and protein depletion by knock-down in Xenopus and knockout in mouse. (A) mRNA and protein expression profile of Xenopus lrp2.L (from Xenbase.org). (B) Xenopus lrp2 expressed in brain (arrowheads), eye anlage, otic vesicle (ov) and proximal pronephros (pn) in stage (st.) 25 tailbud embryo. (C) Morpholino oligomer (MO) decreases Lrp2 expression in injected cells; single channel (C1) for clarity. (D, E) Frontal views of anterior neural folds of wild type (WT; D) and Lrp2-/- (E) mouse embryos at embryonic day (E) 8.5. (D1, E1) WT LRP2 expression (D1) lost in Lrp2-/- (E1). ZO-1 labels cell boundaries. Scale bars (D, E): 50 μm.
	Fig. S2: Mouse neural tube closure phenotypes and CRISPR-Cas9-mediated genome editing of lrp2.L in Xenopus laevis. (A) A putative developmental time line of neural tube (NT) defects (NTDs) in Lrp2-/- mouse embryos. Note that embryos are not strictly to scale between stages, emphasis is on visualization of NTD progression. Top row: wild type (WT) embryos at embryonic day (E) 9.5, 10.5, 12.5, 13.0 and 18.5. Lower rows: Lrp2-/- embryos of the respective stage (st.). Frontal views of heads at E9.5 and inset in E10.5, lateral views of whole embryos at E10.5 through E13.0. E18.5: top views of heads in upper two specimens, lateral view of lower specimen. In all WT embryos from E9.5 onwards, the neural tube was closed (green arrows) and telencephalic neural folds (NF) were fused, creating a continuous dorsal midline (dML; white dotted line). The closed NT has a normal width (green bar). Two phenotypes of Lrp2-/- embryos at E9.5: the NT was either closed with a dilated dML (red bar) or entirely open (red and white dotted lines). Question mark on the dML indicates a putatively open anterior neuropore (ANP), which was not readily visible at E9.5. From E10.5 onwards, three putative “lineages” of development could be tracked: 1) orange markers - embryos with a more or less (±) closed NF and dilated dML (orange arrowheads), readily visible on transverse sections at E12.5 (compare area indicated by green arrowhead in WT and area indicated by orange line in mutant). These embryos most likely gave rise to embryos at E18.5 with a short head and open fontanelle, through which choroid plexus tissue can protrude (cf. Fig. 3A in (Willnow et al., 1996)). 2) red markers - embryos with ± fused NF that had a readily visible opening at the level of the ANP (red arrowheads), visualized via Fgf8 expression in the dML at E10.5 (inset). In such embryos, the open (o) ANP probably increased in size (E13.0), leading to exposure and extrusion of NT tissue (cf. Fig. 2E, (Spoelgen et al., 2005)), finally causing atrophy of anteriormost brain tissue which culminated in an atypical form of anencephaly at E18.5. 3) growth-retarded embryos at E10.5 had open neural folds and probably died after mid-gestation due to cardiovascular defects (Baardman et al., 2016; Christ et al., 2020). Numbers of Lrp2-/- embryos at E9.5 and E10.5 with fused NF and dilated dML (oANP not visible, therefore not scored): 33 / 51, 65 %; with open NF: 18 / 51, 35 %. Embryos at E12.5 and E13.0 with fused NF and dilated dML with a range of closed to wide open ANP: 22 / 22 100 %; no embryos with open NF. Over the past five years, about 2 / 3 of embryos at E18.5 with shortened skull and open fontanelle, 1 / 3 with atypical anencephaly. (B) Schematic representation of Xenopus laevis lrp2.L gene structure; target sequence for single guide (sg) RNA-binding in exon 3 and 4 is shown, protospacer-adjacent motif (PAM) in gray letters. (CJ) Injection of Cas9-ribonucleic particles (CRNP) assembled with sgRNA1 or 2 into zygotes impaired neural plate narrowing and lengthening (C-F) and reduced Lrp2 (G-J) in CRISPants compared to controls. f-Actin marks cell circumference. (K, L) Analysis of sequence flanking target sites confirmed editing in CRNP-injected samples (top row) compared to control samples (lower row).
	Fig. S3: Cell surface area fluctuation during apical constriction. Temporal development of the surface area of individual cells from two independent live-imaged embryos was plotted. Every horizontal bar represents the measurement at one time point (t) of a cell from either the uninjected control side (dark grey) or from the side injected with lrp2MO (identified by lineage tracer fluorescence; magenta). Wherever possible, up to 25 time points representing 120 min of live imaging were measured. For each cell, the cell surface size at t0 was set to 100 % and the relative cell size at the end of the time series is shown. Note that the change in surface area is not continuous and linear (linear development indicated by white rectangles / triangles), but that surface area decreases and increases multiple times before finalizing apical constriction. These fluctuations are pronounced in control cells, but also present in lrp2MOinjected cells.
	Fig. S4: Dynamic planar cell polarity in the Xenopus neural plate. (A) Brightfield image; frontal view of a stage (st.) 15 embryo, note asymmetric pigment accumulation in anterior (a) aspect of cells (outlined by dashed line) in the hindbrain area (arrowheads in A’) compared to symmetric circumferential distribution in forebrain area cells (A’’). (B-D) eYFP-vangl2 was injected into A1-lineage in 4-8-cell embryos and detected using indirect immunofluorescence (IF) for GFP, f-Actin visualizes cell borders. eYFP-Vangl2 localized in dotted, vesicle-like pattern up to st. 16 (B; 6 embryos, st. 14-16). (C) Single forebrain area cell at st. 15, IF demonstrating overlap of Vangl2 and Lrp2 in several spots throughout the cell. (C’) Optical section, level indicated in (C), colored circles indicate overlap. (D) Group of forebrain area cells at st. 17; Vangl2 at membrane, Lrp2 mostly cytoplasmic. (D’) Optical section, level indicated in (D), colored circles indicate (non-)overlap. (E) Re-distribution to (asymmetric) membrane localization from st. 17 onwards (arrowheads in E and E’ indicate Vangl2 asymmetry; 8 embryos, st. 17 / 18). Magnified area (E’) as indicated in (E); (E’1, 2) single channels shown in grayscale. (F) Schematic, describing two aspects of cell polarization - orientation of the long axis of a polarized cell and cell anisotropy. The long axis of a cell can be oriented in anteroposterior (AP; angles 45.1-135˚, light grey) or mediolateral (ML; angles 0-45 and 135.1- 180˚, dark grey) direction. Cells featuring a long axis are anisotropic, with a “roundness” of 0.1 representing a narrow, elongated cell. At 1.0, cells are isotropic and consequentially do not feature a long axis. (G) Assessment of cell polarization during anterior neural fold narrowing in wildtype (WT) embryos from st. 15 to 17. Throughout this time window, cells are anisotropic (magenta numbers), but shift their planar orientation from ML (st. 15) via random (st. 16) to AP (st. 17). (H) Unilateral injection of lrp2MO into the A1-lineage of 8-cell embryos, cell polarity analysis at st. 17. Note anisotropic, AP-oriented cells in control (H’) and more isotropic cells with randomly oriented long axes upon loss of lrp2 (H’’). (I) Graphical representation of reduced anisotropy upon loss of lrp2; Wilcoxon rank sum test, *= ≤0.05. (J, K) Stills from movies of embryos injected with LifeAct at 4-8-cells, T1-transitions between two pairs of cells are visualized over four time points (t). Red arrowheads: shortening cell junction in ML orientation; blue arrowheads: lengthening cell junction in AP orientation. l: left, p: posterior, r: right.
	Fig. S5: Lrp2-interacting scaffold proteins in neural tube closure. (A-D) Immunofluorescence reveals co-localization of LRP2 and NHERF1 on coronal sections of wild type (WT; A, B) and loss of both markers in LRP2-deficient (Lrp2-/-; C, D) mice at embryonic day (E) 8.5 (9 somites). (A1, 2 - D1, 2) Channels shown in grayscale. (E-I) Morpholino oligomer (MO)-mediated gipc1 loss-of-function (LOF) phenocopies the Lrp2 LOF phenotype. 4-8 cell embryos were injected into one dorsal animal blastomere with lineage tracer (LT) and MO / mRNA as indicated; cell borders delineated by f-Actin staining using fluorescently labeled phalloidin. (E’-H’) Cell outlines from boxes indicated in (E-H), colors represent severity of phenotype. No impairment of constriction upon injection of LT (E, E’) or gipc1 (F, F’; green), severe impairment in MO-injected cells (G, G’; red), amelioration of impaired constriction upon re-introduction of gipc1 in MO-injected cells (H, H’; yellow). (I) Graphical representation of experimental data from (A-D), Wilcoxon rank sum test. (J) Magnified views of forebrain area; unilateral injection of gipc1MO similar to (E-H). Note reduction of Vangl2 in morphant cells (10/12 embryos from 5 independent experiments), also evident in transversal optical sections (J’, J’1).
	Movie 1: lrp2 is required for neural tube closure in Xenopus
	Movie 2: lrp2 is required for apical constriction, but dispensable for actin dynamics in the neural plate
	lrp2 (LDL receptor related protein 2) gene expression in X. laevis embryo, NF stage 25, assayed by in situ hybridization, lateral view, anterior left, dorsal up.
	lrp2 (LDL receptor related protein 2) gene expression in X. laevis embryo, NF stage 13, assayed by in situ hybridization, anterior view dorsal up.

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