LRP6 Receptor Plays Essential Functions in Development and Human Diseases

Alrefaei, Abdulmajeed F.; Abu‐Elmagd, Muhammad

doi:10.3390/genes13010120

Cited by 15 publications

(16 citation statements)

References 72 publications

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“…Other reports showed that during development components of the FGF, Wnt, Notch, BPM, and Hedgehog signaling orchestrate crucial cellular events including proliferation, migration, differentiation, epithelial-mesenchymal transition (EMT), morphogenesis and somite myogenesis patterning. When gene expression controlling these events is dysregulated, it leads to disease induction ( Hansson et al, 2004 ; Logan and Nusse, 2004 ; Ma et al, 2010 ; Teven et al, 2014 ; Xiao et al, 2017 ; Abreu de Oliveira et al, 2022 ; Alrefaei and Abu-Elmagd, 2022 ; Towler and Shore, 2022 ). Although our RT did not receive microRNA-related manuscripts, it is well-established that microRNAs play an important role in physiology and disease ( Sayed and Abdellatif, 2011 ; Bhaskaran and Mohan, 2014 ; Kalayinia et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Editorial: Advances in genomic and genetic tools, and their applications for understanding embryonic development and human diseases

Abu‐Elmagd

Assidi

Alrefaei

et al. 2022

Front. Cell Dev. Biol.

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Significant advances have been recently made in the development of the genetic and genomic platforms. This has greatly contributed to a better understanding of gene expression and regulation machinery. Consequently, this led to considerable progress in unraveling evidence of the genotype-phenotype correlation between normal/abnormal embryonic development and human disease complexity. For example, advanced genomic tools such as next-generation sequencing, and microarray-based CGH have substantially helped in the identification of gene and copy number variants associated with diseases as well as in the discovery of causal gene mutations. In addition, bioinformatic analysis tools of genome annotation and comparison have greatly aided in data analysis for the interpretation of the genetic variants at the individual level. This has unlocked potential possibilities for real advances toward new therapies in personalized medicine for the targeted treatment of human diseases. However, each of these genomic and bioinformatics tools has its limitations and hence further efforts are required to implement novel approaches to overcome these limitations. It could be possible that the use of more than one platform for genotype-phenotype deep analysis is an effective approach to disentangling the cause and treatment of the disease complexities. Our research topic aimed at deciphering these complexities by shedding some light on the recent applications of the basic and advanced genetic/genomic and bioinformatics approaches. These include studying gene-gene, protein-protein, and gene-environment interactions. We, in addition, aimed at a better understanding of the link between normal/abnormal embryonic development and the cause of human disease induction.

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Section: Discussionmentioning

confidence: 99%

Editorial: Advances in genomic and genetic tools, and their applications for understanding embryonic development and human diseases

Abu‐Elmagd

Assidi

Alrefaei

et al. 2022

Front. Cell Dev. Biol.

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“…The dysregulation of LRP5 and LRP6 has been associated with various diseases ranging from bone, cardiac, neurodegenerative, diabetes, and hypercholesterolemia to cancer. Though impaired LRP6 signaling is associated with human diseases, studies suggest a predominant role of LRP6 during development, where loss-of-function of LRP6 in mice was embryonically lethal [62][63][64][65].…”

Section: The Lrp Familymentioning

confidence: 99%

“…Furthermore, there is a 98% amino acid sequence similarity between human and mouse LRP6. Furthermore, at the protein level, LRP6 shares more than 93% identity with humans and chickens [63].…”

Section: Evolution Of Lrp5/6mentioning

confidence: 99%

Insights into the Wnt Signaling Pathway Evolution

Rismani¹,

Haghighi-Najafabadi²,

Far³

et al. 2023

Physiology

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Animals’ Wnt signaling pathways are highly preserved signal transduction pathways, which play a crucial role in embryogenesis and adult tissue homeostasis. This chapter reviews the three major Wnt pathways, focusing on some critical proteins in the Wnt/β-catenin path in terms of their evolution and role in homeostasis. Wnt proteins act as a gateway between extracellular, cytoplasmic, and nuclear components to transmit signaling pathways. The Frizzled (FZD) family as G-protein-coupled receptors activates the signaling pathways by binding to Wnt ligands. LRP5/6, members of the family of low-density lipoprotein receptors (LDLR), associate with FZD receptor and Wnt ligands as co-receptors to initiate the Wnt/β-catenin pathway. The Wnt/β-catenin pathway is regulated by antagonists such as the Dickkopf and secreted Frizzled-related protein (SFRP) families.

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“…The Wnt co-receptor Lrp6 acts upstream of β-catenin in the canonical pathway and is required for a wide range of processes pertaining to embryogenesis and organogenesis, including neural tube closure ( Alrefaei and Abu-Elmagd, 2022 ; Carter et al, 2005 ; He et al, 2004 ; Kokubu et al, 2004 ; Mao et al, 2001 ; Pinson et al, 2000 ; Song et al, 2009 , 2010 ; Tamai et al, 2000 ; Wang et al, 2016 ; Wehrli et al, 2000 ; Zhou et al, 2008 , 2004 , 2010 ). Multiple studies have identified mutations in human LRP6 gene from patients with NTDs ( Allache et al, 2014 ; Lei et al, 2015 ; Shi et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

The role of Lrp6-mediated Wnt/β-catenin signaling in the development and intervention of spinal neural tube defects in mice

Zhao

McMahon

Reynolds

et al. 2022

Disease Models &Amp; Mechanisms

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Neural tube defects (NTDs) are among common and severe birth defects with poorly understood etiology. Mutations in the Wnt coreceptor LRP6 are associated with NTDs in humans. Either gain-of-function (GOF) or loss-of-function (LOF) mutations of Lrp6 can cause NTDs in mice. NTDs in Lrp6-GOF mutants may be attributed to altered ß-catenin-independent noncanonical Wnt signaling. However, the mechanisms of NTDs in Lrp6-LOF mutants and the role of Lrp6-mediated canonical Wnt/ß-catenin signaling in neural tube closure remain unresolved. We previously demonstrated that ß-catenin signaling is required for posterior neuropore (PNP) closure. The current study shows that conditional ablation of Lrp6 in dorsal PNP causes spinal NTDs with diminished activities of Wnt/ß-catenin signaling and its downstream target gene Pax3 that is required for PNP closure. ß-catenin-GOF can rescue NTDs in Lrp6-LOF mutants. Moreover, maternal supplementation of a Wnt/ß-catenin signaling agonist can reduce the frequency and severity of spinal NTDs in Lrp6-LOF mutants by restoring Pax3 expression. Together, these results demonstrate the essential role of Lrp6-mediated Wnt/ß-catenin signaling in PNP closure, which may also provide a therapeutic target for NTD intervention through manipulation of canonical Wnt/ß-catenin signaling activities.

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LRP6 Receptor Plays Essential Functions in Development and Human Diseases

Cited by 15 publications

References 72 publications

Editorial: Advances in genomic and genetic tools, and their applications for understanding embryonic development and human diseases

Editorial: Advances in genomic and genetic tools, and their applications for understanding embryonic development and human diseases

Insights into the Wnt Signaling Pathway Evolution

The role of Lrp6-mediated Wnt/β-catenin signaling in the development and intervention of spinal neural tube defects in mice

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