Numb/Numbl-Opo Antagonism Controls Retinal Epithelium Morphogenesis by Regulating Integrin Endocytosis

Bogdanović, Ozren; Delfino‐Machín, Mariana; Nicolás-Pérez, María; Gavilán, María P.; Gago-Rodrigues, Inês; Fernández-Miñán, Ana; Lillo, Concepción; Rı́os, Rosa M.; Wittbrodt, Joachim; Martı́nez-Morales, Juan Ramón

doi:10.1016/j.devcel.2012.09.004

Cited by 68 publications

(82 citation statements)

References 58 publications

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“…Fluorescence in situ hybridization experiments were preformed as previously described 34 . We used the following Cloning of the medaka opo promoter region.…”

Section: Methodsmentioning

confidence: 99%

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Analysis of opo cis-regulatory landscape uncovers Vsx2 requirement in early eye morphogenesis

et al. 2015

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The self-organized morphogenesis of the vertebrate optic cup entails coupling the activation of the retinal gene regulatory network to the constriction-driven infolding of the retinal epithelium. Yet the genetic mechanisms underlying this coordination remain largely unexplored. Through phylogenetic footprinting and transgenesis in zebrafish, here we examine the cis-regulatory landscape of opo, an endocytosis regulator essential for eye morphogenesis. Among the different conserved enhancers identified, we isolate a single retina-specific element (H6_10137) and show that its activity depends on binding sites for the retinal determinant Vsx2. Gain-and loss-of-function experiments and ChIP analyses reveal that Vsx2 regulates opo expression through direct binding to this retinal enhancer. Furthermore, we show that vsx2 knockdown impairs the primary optic cup folding. These data support a model by which vsx2, operating through the effector gene opo, acts as a central transcriptional node that coordinates neural retina patterning and optic cup invagination in zebrafish.

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“…Fluorescence in situ hybridization experiments were preformed as previously described 34 . We used the following Cloning of the medaka opo promoter region.…”

Section: Methodsmentioning

confidence: 99%

“…More recently, biochemical analyses have shown that Opo controls the polarized endocytosis of integrins through interference with the clathrin adaptors Numb and Numbl (ref. 34).…”

mentioning

confidence: 99%

Analysis of opo cis-regulatory landscape uncovers Vsx2 requirement in early eye morphogenesis

et al. 2015

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“…Substitution of the carboxy-terminal tyrosine at position 0 with phenylalanine (or even tryptophan) (Davis et al 1986) has little effect on internalization, whereas a cysteine or alanine change diminishes uptake to that of a cytosolically truncated receptor (Davis et al 1986;Chen et al 1990 [Bogdanovic et al 2012], P-selectin [Ghai et al 2013], ROMK [Fang et al 2009], Sanpodo [Tong et al 2010], and TAT-1 [Nilsson et al 2011] (Fig. 4).…”

Section: Alternative Tyrosine-based Signal Recognition By Ptb-domain-mentioning

confidence: 99%

Cargo Recognition in Clathrin-Mediated Endocytosis

Traub

Bonifacino

2013

Cold Spring Harbor Perspectives in Biology

271

290

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The endosomal system is expansive and complex, characterized by swift morphological transitions, dynamic remodeling of membrane constituents, and intracellular positioning changes. To properly navigate this ever-altering membrane labyrinth, transmembrane protein cargoes typically require specific sorting signals that are decoded by components of protein coats. The best-characterized sorting process within the endosomal system is the rapid internalization of select transmembrane proteins within clathrin-coated vesicles. Endocytic signals consist of linear motifs, conformational determinants, or covalent modifications in the cytosolic domains of transmembrane cargo. These signals are interpreted by a diverse set of clathrin-associated sorting proteins (CLASPs) that translocate from the cytosol to the inner face of the plasma membrane. Signal recognition by CLASPs is highly cooperative, involving additional interactions with phospholipids, Arf GTPases, other CLASPs, and clathrin, and is regulated by large conformational changes and covalent modifications. Related sorting events occur at other endosomal sorting stations.

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“…14,48 Numb has also been implicated in the control of integrin β1 endocytosis during cell migration. 33,34 However, inactivation of the gene encoding integrin β1 in ECs led to hypersprouting in the retinal vasculature, 49 which is the opposite of the Numb/Numbl iECKO phenotype. Numb/Numbl iECKO mice also showed no overt differences in active integrin β1.…”

Section: Discussionmentioning

confidence: 99%

“…32 Numb and Numbl are also known regulators of integrin endocytosis, 33,34 suggesting that defective integrin function might be the cause of vascular defects in Numb/Numbl iECKO mutants. However, immunostaining of activated integrin β1, a subunit that is part of many integrin heterodimers and critical for angiogenesis, 35 was comparable in the P6 control and Numb/Numbl iECKO retinal vasculature (Figure III in the online-only Data Supplement).…”

Section: Analysis Of Notch and Integrin Activity In Numb/numbl Mutantmentioning

confidence: 99%

Regulation of Vascular Endothelial Growth Factor Receptor Function in Angiogenesis by Numb and Numb-Like

Lessen

Nakayama

Kato

et al. 2015

ATVB

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Objective— Vascular endothelial growth factor (VEGF) signaling is a major regulator of physiological and pathological angiogenesis. VEGF receptor activity is strongly controlled by endocytosis, which can terminate or enhance signal transduction in the angiogenic endothelium, but the exact molecular regulation of these processes remains incompletely understood. We have therefore examined the function of Numb family clathrin-associated sorting proteins in angiogenesis. Approach and Results— We show that Numb proteins are expressed by endothelial cells during retinal angiogenesis in mice. Inducible inactivation of the Numb / Numbl genes in the postnatal endothelium led to impaired vessel growth, reduced endothelial proliferation and sprouting, and decreased VEGF receptor activation. Biochemistry and cell biology experiments established that Numb can interact with VEGFR2 and VEGFR3 and controls VEGF receptor activation in response to ligand stimulation. Experiments in cultured endothelial cells showed that Numb proteins counteract VEGF receptor degradation and promote VEGFR2 recycling back to the plasma membrane. Conclusions— Numb proteins control VEGF receptor endocytosis, signaling, and recycling in endothelial cells, which promotes the angiogenic growth of blood vessels.

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Numb/Numbl-Opo Antagonism Controls Retinal Epithelium Morphogenesis by Regulating Integrin Endocytosis

Cited by 68 publications

References 58 publications

Analysis of opo cis-regulatory landscape uncovers Vsx2 requirement in early eye morphogenesis

Analysis of opo cis-regulatory landscape uncovers Vsx2 requirement in early eye morphogenesis

Cargo Recognition in Clathrin-Mediated Endocytosis

Regulation of Vascular Endothelial Growth Factor Receptor Function in Angiogenesis by Numb and Numb-Like

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