ESCRT-II/Vps25 Constrains Digit Number by Endosome-Mediated Selective Modulation of FGF-SHH Signaling

Handschuh, Karen; Feenstra, Jennifer M.; Koss, M. B.; Ferretti, Elisabetta; Risolino, Maurizio; Zewdu, Rediet; Sahai, Michelle A.; Bénazet, Jean-Denis; Peng, Xiao; Depew, Michael J.; Quintana, Laura; Sharpe, James; Wang, Baolin; Alcorn, Heather L.; Rivi, Roberta; Butcher, Stephen; Manak, J. Robert; Vaccari, Thomas; Weinstein, Harel; Anderson, Kathryn V.; Lacy, Elizabeth; Selleri, Licia

doi:10.1016/j.celrep.2014.09.019

Cited by 15 publications

(16 citation statements)

References 62 publications

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“…Given the importance of membrane dynamics in the GC, we next investigated whether ESCRT-II is required for GC endocytosis using a loss-of-function approach. Because ESCRT function is essential for embryonic development [ 44 ], we chose a KD approach. We targeted the Vps25 subunit with a specific splice-blocking antisense morpholino (MO) and achieved a 42 ± 4.3% knockdown as measured by western blot analysis of stage 33/34 eye extracts ( figure 2 a ).…”

Section: Resultsmentioning

confidence: 99%

ESCRT-II controls retinal axon growth by regulating DCC receptor levels and local protein synthesis

et al. 2016

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Endocytosis and local protein synthesis (LPS) act coordinately to mediate the chemotropic responses of axons, but the link between these two processes is poorly understood. The endosomal sorting complex required for transport (ESCRT) is a key regulator of cargo sorting in the endocytic pathway, and here we have investigated the role of ESCRT-II, a critical ESCRT component, in Xenopus retinal ganglion cell (RGC) axons. We show that ESCRT-II is present in RGC axonal growth cones (GCs) where it co-localizes with endocytic vesicle GTPases and, unexpectedly, with the Netrin-1 receptor, deleted in colorectal cancer (DCC). ESCRT-II knockdown (KD) decreases endocytosis and, strikingly, reduces DCC in GCs and leads to axon growth and guidance defects. ESCRT-II-depleted axons fail to turn in response to a Netrin-1 gradient in vitro and many axons fail to exit the eye in vivo. These defects, similar to Netrin-1/DCC loss-of-function phenotypes, can be rescued in whole (in vitro) or in part (in vivo) by expressing DCC. In addition, ESCRT-II KD impairs LPS in GCs and live imaging reveals that ESCRT-II transports mRNAs in axons. Collectively, our results show that the ESCRT-II-mediated endocytic pathway regulates both DCC and LPS in the axonal compartment and suggest that ESCRT-II aids gradient sensing in GCs by coupling endocytosis to LPS.

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Section: Resultsmentioning

confidence: 99%

ESCRT-II controls retinal axon growth by regulating DCC receptor levels and local protein synthesis

et al. 2016

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“…The ESCRT-II subunit Vps25 (Handschuh et al, 2014) does not directly affect Shh secretion. However, degradation of the FGF receptor is perturbed in Vps25 hypomorphic mutants.…”

Section: Functions Of Hedgehog Proteins and Their Related Genes In Timentioning

confidence: 99%

Hedgehog Signal and Genetic Disorders

2019

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The hedgehog (Hh) family comprises sonic hedgehog (Shh), Indian hedgehog (Ihh), and desert hedgehog (Dhh), which are versatile signaling molecules involved in a wide spectrum of biological events including cell differentiation, proliferation, and survival; establishment of the vertebrate body plan; and aging. These molecules play critical roles from embryogenesis to adult stages; therefore, alterations such as abnormal expression or mutations of the genes involved and their downstream factors cause a variety of genetic disorders at different stages. The Hh family involves many signaling mediators and functions through complex mechanisms, and achieving a comprehensive understanding of the entire signaling system is challenging. This review discusses the signaling mediators of the Hh pathway and their functions at the cellular and organismal levels. We first focus on the roles of Hh signaling mediators in signal transduction at the cellular level and the networks formed by these factors. Then, we analyze the spatiotemporal pattern of expression of Hh pathway molecules in tissues and organs, and describe the phenotypes of mutant mice. Finally, we discuss the genetic disorders caused by malfunction of Hh signaling-related molecules in humans.

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“…Despite these advantages, efforts to harness ENU mutagenesis for major phenotypic screening efforts in this species only began in earnest in the 1990’s. A number of different experimental designs have been adopted to identify ENU-induced phenotypes including screens for dominant or recessive mutations (Caspary, 2010; Handschuh et al, 2014; Nolan et al, 2000; Probst and Justice, 2010; Stottmann and Beier, 2010). The experimental protocol has been amenable to both large and small-scale screens, but none have reached genome-wide saturation due to the considerable resources that would be required.…”

Section: Introductionmentioning

confidence: 99%

“…This intraflagellar transport protein gene is also mutated in one type of human ciliopathy termed Short-Rib Thoracic Dysplasia (Norris and Grimes, 2012). Additional ENU mutations have provided new alleles that impact facial development by disrupting signaling through the Wnt, Hh, Tgfb, Fgf, and retinoic acid pathways and are valuable models to understand genetic and environmental influences on human craniofacial birth defects (Bjork et al, 2010; Feng et al, 2013; Handschuh et al, 2014; Sandell et al, 2011; Sandell et al, 2007). Of particular note, a dominant ENU screen identified the mouse line batface (Bfc), which presented with a shorter and broader face and was caused by a mutation in Ctnnb1, the gene encoding β-catenin (Nolan et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…We also suspect that the answer will also be a qualified yes in the long term as forward genetic screens can be used for focused analyses of specific genome regions or in association with other genes or markers to screen for modifiers. Finally, it should also be noted that the high-throughput mouse gene knockout efforts are designed to generate null alleles, whereas ENU mutagenesis has the capability of creating more subtle dominant negative, hypermorphic, or hypomorphic mutations and reveal the role of a gene in craniofacial development that would otherwise be missed using full knockout approaches (Handschuh et al, 2014; Nolan et al, 2000). …”

Section: Introductionmentioning

confidence: 99%

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The old and new face of craniofacial research: How animal models inform human craniofacial genetic and clinical data

Otterloo

Williams

Artinger

2016

Developmental Biology

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The craniofacial skeletal structures that comprise the human head develop from multiple tissues that converge to form the bones and cartilage of the face. Because of their complex development and morphogenesis, many human birth defects arise due to disruptions in these cellular populations. Thus, determining how these structures normally develop is vital if we are to gain a deeper understanding of craniofacial birth defects and devise treatment and prevention options. In this review, we will focus on how animal model systems have been used historically and in an ongoing context to enhance our understanding of human craniofacial development. We do this by first highlighting “animal to man” approaches: that is, how animal models are being utilized to understand fundamental mechanisms of craniofacial development. We discuss emerging technologies, including high throughput sequencing and genome editing, and new animal repository resources, and how their application can revolutionize the future of animal models in craniofacial research. Secondly, we highlight “man to animal” approaches, including the current use of animal models to test the function of candidate human disease variants. Specifically, we outline a common workflow deployed after discovery of a potentially disease causing variant based on a select set of recent examples in which human mutations are investigated in vivo using animal models. Collectively, these topics will provide a pipeline for the use of animal models in understanding human craniofacial development and disease for clinical geneticist and basic researchers alike.

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ESCRT-II/Vps25 Constrains Digit Number by Endosome-Mediated Selective Modulation of FGF-SHH Signaling

Cited by 15 publications

References 62 publications

ESCRT-II controls retinal axon growth by regulating DCC receptor levels and local protein synthesis

ESCRT-II controls retinal axon growth by regulating DCC receptor levels and local protein synthesis

Hedgehog Signal and Genetic Disorders

The old and new face of craniofacial research: How animal models inform human craniofacial genetic and clinical data

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