The Ocular Neural Crest: Specification, Migration, and Then What?

During vertebrate embryonic development, a population of dorsal neural tube-derived stem cells, termed the neural crest (NC), undergo a series of morphogenetic changes and extensive migration to become a diverse array of cell types. Around the developing eye, this multipotent ocular NC cell population, called the periocular mesenchyme (POM), comprises migratory mesenchymal cells that eventually give rise to many of the elements in the anterior of the eye, such as the cornea, sclera, trabecular meshwork, and iris. Molecular cell biology and genetic analyses of congenital eye diseases have provided important information on the regulation of NC contributions to this area of the eye. Nevertheless, a complete understanding of the NC as a contributor to ocular development remains elusive. In addition, positional information during ocular NC migration and the molecular pathways that regulate end tissue differentiation have yet to be fully elucidated. Further, the clinical challenges of ocular diseases, such as Axenfeld-Rieger syndrome (ARS), Peters anomaly (PA) and primary congenital glaucoma (PCG), strongly suggest the need for better treatments. While several aspects of NC evolution have recently been reviewed, this discussion will consolidate the most recent current knowledge on the specification, migration, and contributions of the NC to ocular development, highlighting the anterior segment and the knowledge obtained from the clinical manifestations of its associated diseases. Ultimately, this knowledge can inform translational discoveries with potential for sorely needed regenerative therapies.

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Listeria Pathogenesis and Molecular Virulence Determinants

Clinical Microbiology Reviews ◽

10.1128/cmr.14.3.584-640.2001 ◽

2001 ◽

Vol 14 (3) ◽

pp. 584-640 ◽

Cited By ~ 1350

Author(s):

José A. Vázquez-Boland ◽

Michael Kuhn ◽

Patrick Berche ◽

Trinad Chakraborty ◽

Gustavo Domı́nguez-Bernal ◽

...

Keyword(s):

Life Cycle ◽

Cell Biology ◽

Current Knowledge ◽

Molecular Genetic ◽

Clinical Manifestations ◽

Gravid Uterus ◽

Infection Model ◽

Current View ◽

Immunocompromised Patients ◽

Virulence Determinants

SUMMARY The gram-positive bacterium Listeria monocytogenes is the causative agent of listeriosis, a highly fatal opportunistic foodborne infection. Pregnant women, neonates, the elderly, and debilitated or immunocompromised patients in general are predominantly affected, although the disease can also develop in normal individuals. Clinical manifestations of invasive listeriosis are usually severe and include abortion, sepsis, and meningoencephalitis. Listeriosis can also manifest as a febrile gastroenteritis syndrome. In addition to humans, L. monocytogenes affects many vertebrate species, including birds. Listeria ivanovii, a second pathogenic species of the genus, is specific for ruminants. Our current view of the pathophysiology of listeriosis derives largely from studies with the mouse infection model. Pathogenic listeriae enter the host primarily through the intestine. The liver is thought to be their first target organ after intestinal translocation. In the liver, listeriae actively multiply until the infection is controlled by a cell-mediated immune response. This initial, subclinical step of listeriosis is thought to be common due to the frequent presence of pathogenic L. monocytogenes in food. In normal indivuals, the continual exposure to listerial antigens probably contributes to the maintenance of anti-Listeria memory T cells. However, in debilitated and immunocompromised patients, the unrestricted proliferation of listeriae in the liver may result in prolonged low-level bacteremia, leading to invasion of the preferred secondary target organs (the brain and the gravid uterus) and to overt clinical disease. L. monocytogenes and L. ivanovii are facultative intracellular parasites able to survive in macrophages and to invade a variety of normally nonphagocytic cells, such as epithelial cells, hepatocytes, and endothelial cells. In all these cell types, pathogenic listeriae go through an intracellular life cycle involving early escape from the phagocytic vacuole, rapid intracytoplasmic multiplication, bacterially induced actin-based motility, and direct spread to neighboring cells, in which they reinitiate the cycle. In this way, listeriae disseminate in host tissues sheltered from the humoral arm of the immune system. Over the last 15 years, a number of virulence factors involved in key steps of this intracellular life cycle have been identified. This review describes in detail the molecular determinants of Listeria virulence and their mechanism of action and summarizes the current knowledge on the pathophysiology of listeriosis and the cell biology and host cell responses to Listeria infection. This article provides an updated perspective of the development of our understanding of Listeria pathogenesis from the first molecular genetic analyses of virulence mechanisms reported in 1985 until the start of the genomic era of Listeria research.

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Control of neural crest multipotency by Wnt signaling and the Lin28/let-7 axis

eLife ◽

10.7554/elife.40556 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 12

Author(s):

Debadrita Bhattacharya ◽

Megan Rothstein ◽

Ana Paula Azambuja ◽

Marcos Simoes-Costa

Keyword(s):

Cell Differentiation ◽

Neural Crest ◽

Positional Information ◽

Cell Types ◽

Transcriptional Networks ◽

Dependent Manner ◽

Regulatory Circuit ◽

Distinct Cell ◽

Cell Niche ◽

Migratory Cells

A crucial step in cell differentiation is the silencing of developmental programs underlying multipotency. While much is known about how lineage-specific genes are activated to generate distinct cell types, the mechanisms driving suppression of stemness are far less understood. To address this, we examined the regulation of the transcriptional network that maintains progenitor identity in avian neural crest cells. Our results show that a regulatory circuit formed by Wnt, Lin28a and let-7 miRNAs controls the deployment and the subsequent silencing of the multipotency program in a position-dependent manner. Transition from multipotency to differentiation is determined by the topological relationship between the migratory cells and the dorsal neural tube, which acts as a Wnt-producing stem cell niche. Our findings highlight a mechanism that rapidly silences complex regulatory programs, and elucidate how transcriptional networks respond to positional information during cell differentiation.

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A novel missense mutation of FOXC1 in an Axenfeld–Rieger syndrome patient with a congenital atrial septal defect and sublingual cyst: a case report and literature review

BMC Medical Genomics ◽

10.1186/s12920-021-01103-w ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kaiming Li ◽

Min Tang ◽

Manhua Xu ◽

Yinggui Yu

Keyword(s):

Atrial Septal Defect ◽

Septal Defect ◽

Novel Mutation ◽

Present Report ◽

Anterior Segment ◽

Clinical Manifestations ◽

Hereditary Disease ◽

Congenital Glaucoma ◽

Rieger Syndrome ◽

Sublingual Cyst

Abstract Background Axenfeld–Rieger syndrome (ARS) is a rare autosomal dominant hereditary disease characterized primarily by maldevelopment of the anterior segment of both eyes, accompanied by developmental glaucoma, and other congenital anomalies. FOXC1 and PITX2 genes play important roles in the development of ARS. Case presentation The present report describes a 7-year-old boy with iris dysplasia, displaced pupils, and congenital glaucoma in both eyes. The patient presented with a congenital atrial septal defect and sublingual cyst. The patient’s family has no clinical manifestations. Next generation sequencing identified a pathogenic heterozygous missense variant in FOXC1 gene (NM_001453:c. 246C>A, p. S82R) in the patient. Sanger sequencing confirmed this result, and this mutation was not detected in the other three family members. Conclusion To the best of our knowledge, the results of our study reveal a novel mutation in the FOXC1 gene associated with ARS.

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The cell biology of asthma

The Journal of Cell Biology ◽

10.1083/jcb.201401050 ◽

2014 ◽

Vol 205 (5) ◽

pp. 621-631 ◽

Cited By ~ 162

Author(s):

David J. Erle ◽

Dean Sheppard

Keyword(s):

Smooth Muscle ◽

Epithelial Cells ◽

Airway Obstruction ◽

Cell Biology ◽

Complex Disease ◽

Cultured Cells ◽

Clinical Manifestations ◽

Cell Types ◽

Airway Epithelial Cells ◽

Airway Epithelial

The clinical manifestations of asthma are caused by obstruction of the conducting airways of the lung. Two airway cell types are critical for asthma pathogenesis: epithelial cells and smooth muscle cells. Airway epithelial cells, which are the first line of defense against inhaled pathogens and particles, initiate airway inflammation and produce mucus, an important contributor to airway obstruction. The other main cause of airway obstruction is contraction of airway smooth muscle. Complementary experimental approaches involving cultured cells, animal models, and human clinical studies have provided many insights into diverse mechanisms that contribute to airway epithelial and smooth muscle cell pathology in this complex disease.

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Hoxb3 Regulates Jag1 Expression in Pharyngeal Epithelium and Affects Interaction With Neural Crest Cells

Frontiers in Physiology ◽

10.3389/fphys.2020.612230 ◽

2021 ◽

Vol 11 ◽

Author(s):

Haoran Zhang ◽

Junjie Xie ◽

Karl Kam Hei So ◽

Ka Kui Tong ◽

Jearn Jang Sae-Pang ◽

...

Keyword(s):

Neural Crest ◽

Neural Crest Cells ◽

Positional Information ◽

Cell Types ◽

Cellular Interaction ◽

Pharyngeal Arch ◽

Surface Ectoderm ◽

Pharyngeal Arches ◽

Elevated Expression ◽

Pharyngeal Epithelium

Craniofacial morphogenesis depends on proper migration of neural crest cells and their interactions with placodes and other cell types. Hox genes provide positional information and are important in patterning the neural crest and pharyngeal arches (PAs) for coordinated formation of craniofacial structures. Hox genes are expressed in the surface ectoderm and epibranchial placodes, their roles in the pharyngeal epithelium and their downstream targets in regulating PA morphogenesis have not been established. We altered the Hox code in the pharyngeal region of the Hoxb3Tg/+ mutant, in which Hoxb3 is driven to ectopically expressed in Hoxb2 domain in the second pharyngeal arch (PA2). In the transgenic mutant, ectopic Hoxb3 expression was restricted to the surface ectoderm, including the proximal epibranchial placodal region and the distal pharyngeal epithelium. The Hoxb3Tg/+ mutants displayed hypoplasia of PA2, multiple neural crest-derived facial skeletal and nerve defects. Interestingly, we found that in the Hoxb3Tg/+ mutant, expression of the Notch ligand Jag1 was specifically up-regulated in the ectodermal pharyngeal epithelial cells of PA2. By molecular experiments, we demonstrated that Hoxb3 could bind to an upstream genomic site S2 and directly regulate Jag1 expression. In the Hoxb3Tg/+ mutant, elevated expression of Jag1 in the pharyngeal epithelium led to abnormal cellular interaction and deficiency of neural crest cells migrating into PA2. In summary, we showed that Hoxb3 regulates Jag1 expression and proposed a model of pharyngeal epithelium and neural crest interaction during pharyngeal arch development.

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The Impact of Estrogen and Estrogen-Like Molecules in Neurogenesis and Neurodegeneration: Beneficial or Harmful?

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.636176 ◽

2021 ◽

Vol 15 ◽

Author(s):

Felipe A. Bustamante-Barrientos ◽

Maxs Méndez-Ruette ◽

Alexander Ortloff ◽

Patricia Luz-Crawford ◽

Francisco J. Rivera ◽

...

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptors ◽

Cell Biology ◽

Current Knowledge ◽

Cell Types ◽

Proliferation And Differentiation ◽

Neural Stem Progenitor Cells ◽

The Central Nervous System ◽

Health And Disease ◽

The Impact

Estrogens and estrogen-like molecules can modify the biology of several cell types. Estrogen receptors alpha (ERα) and beta (ERβ) belong to the so-called classical family of estrogen receptors, while the G protein-coupled estrogen receptor 1 (GPER-1) represents a non-classical estrogen receptor mainly located in the plasma membrane. As estrogen receptors are ubiquitously distributed, they can modulate cell proliferation, differentiation, and survival in several tissues and organs, including the central nervous system (CNS). Estrogens can exert neuroprotective roles by acting as anti-oxidants, promoting DNA repair, inducing the expression of growth factors, and modulating cerebral blood flow. Additionally, estrogen-dependent signaling pathways are involved in regulating the balance between proliferation and differentiation of neural stem/progenitor cells (NSPCs), thus influencing neurogenic processes. Since several estrogen-based therapies are used nowadays and estrogen-like molecules, including phytoestrogens and xenoestrogens, are omnipresent in our environment, estrogen-dependent changes in cell biology and tissue homeostasis have gained attention in human health and disease. This article provides a comprehensive literature review on the current knowledge of estrogen and estrogen-like molecules and their impact on cell survival and neurodegeneration, as well as their role in NSPCs proliferation/differentiation balance and neurogenesis.

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Genetics Underlying the Interactions between Neural Crest Cells and Eye Development

Journal of Developmental Biology ◽

10.3390/jdb8040026 ◽

2020 ◽

Vol 8 (4) ◽

pp. 26

Author(s):

Jochen Weigele ◽

Brenda L. Bohnsack

Keyword(s):

Neural Crest ◽

Anterior Segment ◽

Neural Crest Cell ◽

Neural Crest Cells ◽

Eye Diseases ◽

Stem Cell Population ◽

Ocular Development ◽

Early Migration ◽

Optic Cup ◽

Crest Cell

The neural crest is a unique, transient stem cell population that is critical for craniofacial and ocular development. Understanding the genetics underlying the steps of neural crest development is essential for gaining insight into the pathogenesis of congenital eye diseases. The neural crest cells play an under-appreciated key role in patterning the neural epithelial-derived optic cup. These interactions between neural crest cells within the periocular mesenchyme and the optic cup, while not well-studied, are critical for optic cup morphogenesis and ocular fissure closure. As a result, microphthalmia and coloboma are common phenotypes in human disease and animal models in which neural crest cell specification and early migration are disrupted. In addition, neural crest cells directly contribute to numerous ocular structures including the cornea, iris, sclera, ciliary body, trabecular meshwork, and aqueous outflow tracts. Defects in later neural crest cell migration and differentiation cause a constellation of well-recognized ocular anterior segment anomalies such as Axenfeld–Rieger Syndrome and Peters Anomaly. This review will focus on the genetics of the neural crest cells within the context of how these complex processes specifically affect overall ocular development and can lead to congenital eye diseases.

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Tail Regeneration in Xenopus laevis as a Model for Understanding Tissue Repair

Journal of Dental Research ◽

10.1177/154405910808700909 ◽

2008 ◽

Vol 87 (9) ◽

pp. 806-816 ◽

Cited By ~ 47

Author(s):

A.-S. Tseng ◽

M. Levin

Keyword(s):

Xenopus Laevis ◽

Cell Biology ◽

Traumatic Injury ◽

Embryonic Stem ◽

Cell Types ◽

Tail Regeneration ◽

Tadpole Tail ◽

Adult Organism ◽

Regenerative Therapies ◽

Bioelectric Signals

Augmentation of regenerative ability is a powerful strategy being pursued for the biomedical management of traumatic injury, cancer, and degeneration. While considerable attention has been focused on embryonic stem cells, it is clear that much remains to be learned about how somatic cells may be controlled in the adult organism. The tadpole of the frog Xenopus laevis is a powerful model system within which fundamental mechanisms of regeneration are being addressed. The tadpole tail contains spinal cord, muscle, vasculature, and other terminally differentiated cell types and can fully regenerate itself through tissue renewal—a process that is most relevant to mammalian healing. Recent insight into this process has uncovered fascinating molecular details of how a complex appendage senses injury and rapidly repairs the necessary morphology. Here, we review what is known about the chemical and bioelectric signals underlying this process and draw analogies to evolutionarily conserved pathways in other patterning systems. The understanding of this process is not only of fundamental interest for the evolutionary and cell biology of morphogenesis, but will also generate information that is crucial to the development of regenerative therapies for human tissues and organs.

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Primary cilia deficiency in neural crest cells causes Anterior Segment Dysgenesis

10.1101/752105 ◽

2019 ◽

Author(s):

Céline Portal ◽

Peter Lwigale ◽

Panteleimon Rompolas ◽

Carlo Iomini

Keyword(s):

Neural Crest ◽

Primary Cilium ◽

Primary Cilia ◽

Anterior Segment ◽

Corneal Stroma ◽

Neural Crest Cells ◽

Corneal Neovascularization ◽

Congenital Glaucoma ◽

Anterior Segment Dysgenesis ◽

Hh Signaling

ABSTRACTDuring eye embryogenesis, neural crest cells (NCC) of the periocular mesenchyme (POM) migrate to the anterior segment (AS) of the eye and then differentiate into the corneal stroma and endothelium, ciliary body, iris stroma, and the trabecular meshwork. Defective development of these structures leads to anterior segment dysgenesis (ASD) that in 50% of the cases leads to glaucoma, a leading cause of blindness. Here, we show that the primary cilium is indispensable for normal AS development and that its ablation in NCC induces ASD phenotypes including; small and thin cornea, impaired stromal keratocyte organization, abnormal iridocorneal angle with reduced anterior chamber and corneal neovascularization. These defects are similar to those described in patients with AS conditions such as Axenfeld-Rieger syndrome and Peter’s anomaly. Mechanistically, disruption of the primary cilium in the NCC resulted in reduced hedgehog (Hh) signaling in the POM, canonically activated by the Indian Hedgehog ligand expressed by endothelial cells of the choroid. This caused decreased cell proliferation in a subpopulation of POM cells surrounding the retinal pigmented epithelium. Moreover, primary cilium ablation in NCC also led to a decreased expression of Foxc1 and Pitx2, two transcription factors identified as major ASD causative genes. These findings suggest that primary cilia are indispensable for NCC to form normal AS structures via Hh signaling. Defects in primary cilia could, therefore, contribute to the pathogenesis of ASD, and to their complications such as congenital glaucoma.

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Pan-American Lancehead Pit-Vipers: Coagulotoxic Venom Effects and Antivenom Neutralisation of Bothrops asper and B. atrox Geographical Variants

Toxins ◽

10.3390/toxins13020078 ◽

2021 ◽

Vol 13 (2) ◽

pp. 78

Author(s):

Lachlan A. Bourke ◽

Christina N. Zdenek ◽

Edgar Neri-Castro ◽

Melisa Bénard-Valle ◽

Alejandro Alagón ◽

...

Keyword(s):

Evolutionary Biology ◽

Current Knowledge ◽

Clinical Manifestations ◽

In Vivo Studies ◽

Factor X ◽

Clotting Factors ◽

Bothrops Asper ◽

Species Specific

The toxin composition of snake venoms and, thus, their functional activity, can vary between and within species. Intraspecific venom variation across a species’ geographic range is a major concern for antivenom treatment of envenomations, particularly for countries like French Guiana that lack a locally produced antivenom. Bothrops asper and Bothrops atrox are the most medically significant species of snakes in Latin America, both producing a variety of clinical manifestations, including systemic bleeding. These pathophysiological actions are due to the activation by the venom of the blood clotting factors Factor X and prothrombin, thereby causing severe consumptive coagulopathy. Both species are extremely wide-ranging, and previous studies have shown their venoms to exhibit regional venom variation. In this study, we investigate the differential coagulotoxic effects on human plasma of six venoms (four B. asper and two B. atrox samples) from different geographic locations, spanning from Mexico to Peru. We assessed how the venom variation of these venom samples affects neutralisation by five regionally available antivenoms: Antivipmyn, Antivipmyn-Tri, PoliVal-ICP, Bothrofav, and Soro Antibotrópico (SAB). The results revealed both inter- and intraspecific variations in the clotting activity of the venoms. These variations in turn resulted in significant variation in antivenom efficacy against the coagulotoxic effects of these venoms. Due to variations in the venoms used in the antivenom production process, antivenoms differed in their species-specific or geographical neutralisation capacity. Some antivenoms (PoliVal-ICP, Bothrofav, and SAB) showed species-specific patterns of neutralisation, while another antivenom (Antivipmyn) showed geographic-specific patterns of neutralisation. This study adds to current knowledge of Bothrops venoms and also illustrates the importance of considering evolutionary biology when developing antivenoms. Therefore, these results have tangible, real-world implications by aiding evidence-based design of antivenoms for treatment of the envenomed patient. We stress that these in vitro studies must be backed by future in vivo studies and clinical trials before therapeutic guidelines are issued regarding specific antivenom use in a clinical setting.

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