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A Novel Multistep Mechanism for Initial Lymphangiogenesis in Mouse Embryos Based on Ultramicroscopy

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A Novel Multistep Mechanism for Initial Lymphangiogenesis in Mouse Embryos Based on Ultramicroscopy View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Wageningen University & Research Publications The EMBO Journal (2013) 32, 629–644 www.embojournal.org THE EMBO JOJOURNALUR NAL A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy Rene´ Ha¨ gerling1,7, Cathrin Pollmann1,7, Introduction Martin Andreas1, Christian Schmidt1, 2 3 2 Lymphatic vessels, the second vascular system of vertebrates, Harri Nurmi , Ralf H Adams , Kari Alitalo , are indispensable for tissue homeostasis. The lymphatic Volker Andresen4, Stefan Schulte-Merker5,6 1, vasculature collects and returns extravasated fluids, proteins, and Friedemann Kiefer * dietary lipids and immune cells into the venous circulation. 1Mammalian Cell Signaling Laboratory, Department of Vascular Cell Failure of the lymphatic vessels to develop or function is Biology, Max Planck Institute for Molecular Biomedicine, Mu¨nster, associated with a severe impairment of fluid homeostasis, 2 Germany, Molecular/Cancer Biology Laboratory, Biomedicum tissue integrity and the generation of immune responses Helsinki, University of Helsinki, Helsinki, Finland, 3Department of et al Tissue Morphogenesis, Faculty of Medicine, Max Planck Institute for (Tammela and Alitalo, 2010; Schulte-Merker , 2011). Molecular Biomedicine, University of Mu¨nster, Mu¨nster, Germany, Although blood and lymphatic vessels exist and operate in 4LaVision BioTec GmbH, Bielefeld, Germany, 5Developmental Biology, close proximity, it is vital for their function to remain as 6 Hubrecht Institute, CT Utrecht, The Netherlands and EZO, University separate entities. Both systems only connect at the subclavian of Wageningen, The Netherlands veins, where the thoracic duct (TD) and right lymphatic duct drain into the venous blood vasculature. During mammalian development, a subpopulation of Lymphatic endothelial cells (LECs) differentiate from blood endothelial cells in the cardinal vein (CV) expresses lym- endothelial cells (BECs) in the cardinal vein (CV) after the phatic-specific genes and subsequently develops into the onset of circulation. In the mouse, differentiation of LECs first lymphatic structures, collectively termed as lymph starts around day 9.0 of embryonic development (E9.0) by sacs. Budding, sprouting and ballooning of lymphatic polarized expression of the transcription factor Sox18 in endothelial cells (LECs) have been proposed to underlie dorsolateral cells of the CV (Francois et al, 2008), where the emergence of LECs from the CV, but the exact mechan- Sox18 induces expression of the transcription factor Prox1. isms of lymph vessel formation remain poorly understood. Prox1 becomes detectable in the CV around E10.0 and Prox1- Applying selective plane illumination-based ultramicro- expressing LECs emerge from the CV and migrate dorsally, scopy to entire wholemount-immunostained mouse where they form the first lymphatic structures (Oliver, 2004). embryos, we visualized the complete developing vascular Prox1-deficient embryos completely lack lymphatic devel- system with cellular resolution. Here, we report emer- opment due to a failure in LECs specification (Wigle et al, gence of the earliest detectable LECs as strings of loosely 2002). Acting as a master regulator of lymphatic develop- connected cells between the CV and superficial venous ment, forced Prox1 expression in cultured BECs confers plexus. Subsequent aggregation of LECs resulted in for- lymphatic identity (Hong et al, 2002; Petrova et al, 2002). mation of two distinct, previously unidentified lymphatic At present, the signals responsible for the polarized structures, the dorsal peripheral longitudinal lymphatic expression of Sox18 and Prox1 in the CV are unknown. vessel (PLLV) and the ventral primordial thoracic duct Furthermore, directed migration of the emerging LECs (pTD), which at later stages formed a direct contact with depends on the vascular endothelial growth factor C (VEGF-C), the CV. Providing new insights into their function, we À À which is provided by the lateral mesoderm. Also, Vegf-c / found vascular endothelial growth factor C (VEGF-C) and þ À mouse embryos lack lymphatic vessels and Vegf-c / mice the matrix component CCBE1 indispensable for LEC bud- suffer from lymphatic hypoplasia, demonstrating haplo- ding and migration. Altogether, we present a significantly insufficiency of a single Vegf-c allele for lymphatic more detailed view and novel model of early lymphatic development (Karkkainen et al, 2004). VEGF-C acts via its development. tyrosine kinase receptor vascular endothelial growth factor The EMBO Journal (2013) 32, 629–644. doi:10.1038/ receptor 3 (VEGFR-3) and the non-signalling coreceptor emboj.2012.340; Published online 8 January 2013 neuropilin 2 (Nrp2) (Karpanen et al, 2006; Tammela et al, Subject Categories: development 2010). Extracellular cues for emerging LECs are provided by Keywords: lymph vessel development; ultramicroscopy; the matrix-interacting protein collagen and calcium-binding VEGFR-3; CCBE1; VEGF-C EGF domains 1 (CCBE1), which in a non-cell autonomous fashion strongly augments the pro-lymphangiogenic activity of VEGF-C (Bos et al, 2011). In the mouse also CCBE1 is indispensable for lymphatic development because Prox1- *Corresponding author. Department of Vascular Cell Biology, Max À / À Planck Institute for Molecular Biomedicine, Ro¨ntgenstrasse 20, 48149 expressing Ccbe1 endothelial cells fail to leave the CV Mu¨nster, Germany. Tel.: þ49 251 70365 230; Fax: þ49 251 70365 297; and migrate (Bos et al, 2011). E-mail: [email protected] Elegant genetic studies and lineage tracing experiments 7 These authors contributed equally to this work. have confirmed the venous origin of LECs first proposed by Received: 3 May 2012; accepted: 5 December 2012; published online: Sabin over 100 years ago (Sabin, 1902; Wigle and Oliver, 8 January 2013 1999; Srinivasan et al, 2007). Yet, despite significant advances &2013 European Molecular Biology Organization The EMBO Journal VOL 32 | NO 5 | 2013 629 Visualizing first lymph vessels by ultramicroscopy RHa¨gerling et al in the identification of genes involved in the formation of the overcome the limitations associated with the analysis of first lymphatic vessels (reviewed in Schulte-Merker et al, consecutive tissue sections, we employed ultramicroscopy, 2011), the exact morphogenetic mechanisms of initial a technology that has become recently commercially avail- lymphangiogenesis remain incompletely understood. The able. Ultramicroscopy is a planar illumination microscopy initial analysis of Prox1-deficient mice suggested budding of technique, which enabled us to perform optical sectioning newly specified LECs from the CV, followed by dorsal of immunostained, cleared, intact mouse embryos at migration and reorganization into large lumenized E9.5–E12.0. Illumination with a laminar sheet of light causes structures termed as lymph sacs (Oliver, 2004). the excitation of a thin sample plane, which is recorded Unexpectedly, several genes, some of which are exclusively orthogonally to the illumination light path by widefield expressed in haematopoietic cells (Abtahian et al, 2003; imaging with an area detector, in our case an EM-CCD Bohmer et al, 2010), have been shown to be important for camera. Ultramicroscopy is particularly suited for the analy- the separation of blood and lymphatic vessels. These include sis of developmental processes in large specimen. Because the lymphatic transmembrane glycoprotein podoplanin (Fu axial and lateral resolution scale with the inverse numerical et al, 2008; Uhrin et al, 2010) and its pro-coagulant receptor aperture of the illumination and detection optics (1/NAill and on platelets, CLEC-2 (reviewed in D’Amico and Alitalo, 2010). 1/NAdet) both parameters can be adjusted to obtain an The involvement of platelets in the separation of blood and isotropic point spread function when using this technology lymph vessels sparked a new concept, which proposed LECs (Supplementary Figure 1). Despite the use of low magnifica- to emerge from the CV by sprouting. Platelet coagulation at tion and low numerical aperture optics, image stacks cover- the base of emerging sprouts was hypothesized to trigger the ing entire wholemount immunostained mouse embryos with subsequent abscission of newly formed lymphatic vessels comparable lateral and axial resolution reaching the level of from the CV (Kim and Koh, 2010; Uhrin et al, 2010). Finally, individual cells were obtained (Figure 1A–D). optical projection tomography reconstructions suggested entire segmental areas of the CV to balloon out and pinch The first lymphatic endothelial progenitors emerge as off dorsally. Again aided by platelets, this morphogenetic streams of cells from the roof of the CV process would give rise to lymph sacs in a single step To identify landmark structures of the developing vascular (Francois et al, 2012). Presently, due to these conflicting system, we performed wholemount immunostaining for models the precise mechanism of the first steps of PECAM-1, which was expressed on all vessels, however, lymphatic vessel formation remains unclear and requires with varying intensity. Invariably, arterial vessels displayed novel analytical approaches. the strongest PECAM-1 expression followed by veins, while In the mouse, progress in understanding lymphatic devel- the lymphatic vessels showed weakest expression. Therefore, opment has been hampered by limited imaging access. In this strong PECAM-1 staining depicted the arterial vasculature in
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