Organ‐specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene‐targeting of the PI3K regulatory isoforms p85α, p55α, and p50α

Mouta-Bellum, Carla; Kirov, Aleksander; Miceli-Libby, Laura; Mancini, Maria; Petrova, Tatiana V.; Liaw, Lucy; Prudovsky, Igor; Miura, Naoyuki; Cantley, Lewis C.; Alitalo, Kari; Fruman, David A.; Vary, Calvin P.H.

doi:10.1002/dvdy.22078

Cited by 55 publications

(46 citation statements)

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“…It remains a possibility that signaling through AKT may be utilized downstream of Flt4 at later stages of lymphatic morphogenesis or maintenance. Indeed, signaling through the phosphoinositide 3-kinase (PI3K) pathway, an essential upstream activator of AKT, has been implicated in both mice and humans at later stages of lymphatic morphogenesis and maintenance, and in an organ-specific manner (Boscolo et al, 2015;Mouta-Bellum et al, 2009). Thus, although these studies suggest that it is likely that AKT plays an important role in lymphatic development, our findings rule out this effector during the earliest steps of trunk lymphatic development.…”

Section: Discussionmentioning

confidence: 99%

Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors

et al. 2016

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There was an error published in Development 143, 3785-3795.In the Materials and Methods section we provided an incorrect serine residue number for the map2k2b mutation. The corrected section of text is as follows:An activated myc-tagged form of MEK was generated from zebrafish map2k2b by mutating serines 221 and 225 to aspartic acid (Schramek et al., 1997) by PCR, followed by BP cloning to generate pME-myc-act-map2k2b.In addition, we have since verified that the pME-myc-act-map2k2b plasmid used in the original studies and submitted to Addgene contains the correct sequence. This plasmid contains several nucleotide changes in comparison to the GenBank reference sequence (accession number: NM_001128281). However, all of these changes have been noted in a previous annotation of single nucleotide polymorphisms in the zebrafish and are naturally occurring variants (Butler et al., 2015).We apologize for any confusion that this may have caused and we thank the researchers who discovered the error for bringing it to our attention. ABSTRACTVascular endothelial growth factor C (Vegfc) activates its receptor, Flt4, to induce lymphatic development. However, the signals that act downstream of Flt4 in this context in vivo remain unclear. To understand Flt4 signaling better, we generated zebrafish bearing a deletion in the Flt4 cytoplasmic domain that eliminates tyrosines Y1226 and 1227. Embryos bearing this deletion failed to initiate sprouting or differentiation of trunk lymphatic vessels and did not form a thoracic duct. Deletion of Y1226/7 prevented ERK phosphorylation in lymphatic progenitors, and ERK inhibition blocked trunk lymphatic sprouting and differentiation. Conversely, endothelial autonomous ERK activation rescued lymphatic sprouting and differentiation in flt4 mutants. Interestingly, embryos bearing the Y1226/7 deletion formed a functional facial lymphatic network enabling them to develop normally to adulthood. By contrast, flt4 null larvae displayed hypoplastic facial lymphatics and severe lymphedema. Thus, facial lymphatic vessels appear to be the first functional lymphatic network in the zebrafish, whereas the thoracic duct is initially dispensable for lymphatic function. Moreover, distinct signaling pathways downstream of Flt4 govern lymphatic morphogenesis and differentiation in different anatomical locations.

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Section: Discussionmentioning

confidence: 99%

Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors

et al. 2016

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“…Pik3r1 regulatory subunit display defects in lymphatic remodeling and maturation, while lymphatic vessels display upregulation of biliary EC markers such as endoglin (36).…”

Section: Discussionmentioning

confidence: 99%

Endothelial ERK signaling controls lymphatic fate specification

Deng

Atri²,

Eichmann³

et al. 2013

J. Clin. Invest.

117

103

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“…Vascular endothelial growth factors-C and -D may also stimulate lymphangiogenesis [13] . Mutations in the FOXC2 (MFH-1) gene or deletion of the pik3r1 gene may result in lymphangiectasia, arrested lymphatic sprouting and maturation defects [14,15] . Defects in chromosome 4 may be related to Rieger syndrome, head and neck squamous cell carcinoma and postoperative atrial fibrillation [16][17][18] .…”

Section: Discussionmentioning

confidence: 99%

Primary intestinal lymphangiectasia diagnosed by capsule endoscopy and double balloon enteroscopy

Oh¹

2011

WJGE

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Author contributions: Oh TG designed the case report as a main author; Chung JW and Kim HM contributed to provide background knowledge; Han SJ provided many informations about the patient; Lee JS provided genetic information and accessment; Park JY participated in endoscopic evaluation and accessment; Song SY supervised and checked up the manuscript finally as a corresponding author; all authors reviewed and approved the final manuscript. AbstractPrimary intestinal lymphangiectasia (PIL) is a rare disorder characterized by dilated intestinal lymphatics and the development of protein-losing enteropathy. Patients with PIL develop hypoalbuminemia, hypocalcemia, lymphopenia and hypogammaglobulinemia, and present with bilateral lower limb edema, fatigue, abdominal pain and diarrhea. Endoscopy reveals diffusely elongated, circumferential and polypoid mucosae covered with whitish enlarged villi, all of which indicate intestinal lymphangiectasia. Diagnosis is confirmed by characteristic tissue pathology, which includes dilated intestinal lymphatics with diffusely swollen mucosa and enlarged villi. The prevalence of PIL has increased since the introduction of capsule endoscopy. The etiology and prevalence of PIL remain unknown. Some studies have reported that several genes and regulatory molecules for lymphangiogenesis are related to PIL. We report the case of a patient with PIL involving the entire small bowel that was confirmed by capsule endoscopy and double-balloon enteroscopy-guided tissue pathology who carried a deletion on chromosome 4q25. The relationship between this deletion on chromosome 4 and PIL remains to be investigated.

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Organ‐specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene‐targeting of the PI3K regulatory isoforms p85α, p55α, and p50α

Cited by 55 publications

References 46 publications

Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors

Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors

Endothelial ERK signaling controls lymphatic fate specification

Primary intestinal lymphangiectasia diagnosed by capsule endoscopy and double balloon enteroscopy

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