Identification of lens-regulated genes driving anterior eye development.

Signals from the lens regulate multiple aspects of eye development, including establishment of eye size, patterning of the presumptive iris and ciliary body in the anterior optic cup and migration and differentiation of neural crest cells. To advance understanding of the molecular mechanism by which the lens regulates eye development, we performed transcriptome profiling of embryonic chicken retinas after lens removal. Genes associated with nervous system development were upregulated in lens-removed eyes, but the presumptive ciliary body and iris region did not adopt a neural retina identity following lens removal.

Assessment of the Teratogenic Effect of Drugs on the Chicken Embryo.

Pre-clinical trials are an essential step that underpins the drug discovery, development, and safety process. During this process, animal testing is performed to determine the safety of new compounds and any potential adverse effects. Developmental toxicity tests are carried out to verify whether the drug has potential to cause congenital anomalies to the developing embryo/fetus.

Considerations for future quantitative structure-activity relationship (QSAR) modelling for heavy metals - A case study of mercury.

With increasing annual chemical development and production, safety testing demands and requirements have also increased. In addition to traditional animal testing, quantitative structure-activity relationship (QSAR) modelling can be used to predict the biological effect of a chemical structure, based on the analysis of quantitative characteristics of structure features. Whilst suitable for e.

Teratogenicity and Reactive Oxygen Species after transient embryonic hypoxia: Experimental and clinical evidence with focus on drugs causing failed abortion in humans.

Teratogenicity and Reactive Oxygen Species after transient embryonic hypoxia: Experimental and clinical evidence with focus on drugs with human abortive potential. Reactive Oxygen Species (ROS) can be harmful to embryonic tissues. The adverse embryonic effects are dependent on the severity and duration of the hypoxic event and when during organongenesis hypoxia occurs.

Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA.

Despite whole-genome sequencing (WGS), many cases of single-gene disorders remain unsolved, impeding diagnosis and preventative care for people whose disease-causing variants escape detection. Since early WGS data analytic steps prioritize protein-coding sequences, to simultaneously prioritize variants in non-coding regions rich in transcribed and critical regulatory sequences, we developed GROFFFY, an analytic tool that integrates coordinates for regions with experimental evidence of functionality. Applied to WGS data from solved and unsolved hereditary hemorrhagic telangiectasia (HHT) recruits to the 100,000 Genomes Project, GROFFFY-based filtration reduced the mean number of variants/DNA from 4,867,167 to 21,486, without deleting disease-causal variants.

A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders.

The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-inflammatory actions. These actions, in large part, are mediated by IMiD binding to the human protein cereblon that forms a critical component of the E3 ubiquitin ligase complex. This complex ubiquitinates and thereby regulates the levels of multiple endogenous proteins.

Thalidomide upper limb embryopathy - pathogenesis, past and present management and future considerations.

This review article provides a comprehensive overview of thalidomide upper limb embryopathy including updates about its pathogenesis, a historical account of the management of the paediatric thalidomide patient, experience with management of the adult patient, as well as creating awareness about early onset age-related changes associated with limb differences. Despite its withdrawal from the market in November 1961, novel discoveries have meant thalidomide is licensed again and currently still in use to treat a variety of conditions, including inflammatory disorders and some cancers. Yet, if not used safely, thalidomide still has the potential to cause damage to the embryo.

Novel, thalidomide-like, non-cereblon binding drug tetrafluorobornylphthalimide mitigates inflammation and brain injury.

Background: Quelling microglial-induced excessive neuroinflammation is a potential treatment strategy across neurological disorders, including traumatic brain injury (TBI), and can be achieved by thalidomide-like drugs albeit this approved drug class is compromised by potential teratogenicity. Tetrafluorobornylphthalimide (TFBP) and tetrafluoronorbornylphthalimide (TFNBP) were generated to retain the core phthalimide structure of thalidomide immunomodulatory imide drug (IMiD) class. However, the classical glutarimide ring was replaced by a bridged ring structure.

From the Farm to the Lab: How Chicken Embryos Contribute to the Field of Teratology.

Congenital anomalies and its causes, particularly, by external factors are the aim of the field called teratology. The external factors studied by teratology are known as teratogens and can be biological or environmental factors for example, chemicals, medications, recreational drugs, environmental pollutants, physical agents (e.g.

Lewis Wolpert (1929-2021).

Lewis Wolpert was a brilliant and inspiring scientist who made hugely significant contributions which underpin and influence our understanding of developmental biology today. He spent his career interested in how the fertilised egg can give rise to the whole embryo (and ultimately the adult) with one head, two arms, two legs, all its organs and importantly how cells become different from each other and how they 'know' what to become. His ideas revolutionised the way developmental biology was perceived and also reinvigorated, in particular, the key question of how pattern formation in embryonic development is achieved.

Knockdown of slit signaling during limb development leads to a reduction in humerus length.

Background: Slits (1-3) and their Robo (1-3) receptors play multiple non-neuronal roles in development, including in development of muscle, heart and mammary gland. Previous work has demonstrated expression of Slit and Robo family members during limb development, where their functions are unclear.

Results: In situ hybridisation confirmed strong expression of Slit2, Slit3, Robo1, and Robo2 throughout mouse limb and joint development.

Antiangiogenic Activity and in Silico Cereblon Binding Analysis of Novel Thalidomide Analogs.

Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomide analogs was evaluated for antiangiogenic activity in an ex vivo rat aorta ring assay. The protein cereblon has been identified as the target for thalidomide, and in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs.

Genetic association and characterization of FSTL5 in isolated clubfoot.

Talipes equinovarus (clubfoot, TEV) is a congenital rotational foot deformity occurring in 1 per 1000 births with increased prevalence in males compared with females. The genetic etiology of isolated clubfoot (iTEV) remains unclear. Using a genome-wide association study, we identified a locus within FSTL5, encoding follistatin-like 5, significantly associated with iTEV.

Role of cereblon in angiogenesis and in mediating the antiangiogenic activity of immunomodulatory drugs.

Cereblon (CRBN) is a substrate recruiter element of the E3 cullin 4-RING ubiquitin ligase complex, and a binding target of immunomodulatory agents (IMiDs). CRBN is responsible for the pleiotropic effects of IMiDs, yet its function in angiogenesis and in mediating the antiangiogenic effects of IMiDs remains unclear. We investigated the role of CRBN in the angiogenic process and in propagating the antiangiogenic effects of IMiDs in vitro.

Positional Information-A concept underpinning our understanding of developmental biology.

It is now 50 years since Lewis Wolpert published the paper in which he set out the concept of Positional Information to explain how spatial patterns of cellular differentiation are generated. This concept has provided a universal model for pattern formation in embryonic development and regeneration and become part of the fabric of the field of developmental biology. Here I outline how Wolpert devised the concept of Positional Information and describe landmark studies from his lab investigating how Positional Information is specified in the developing chick limb.

VGLL3 operates via TEAD1, TEAD3 and TEAD4 to influence myogenesis in skeletal muscle.

VGLL proteins are transcriptional co-factors that bind TEAD family transcription factors to regulate events ranging from wing development in fly, to muscle fibre composition and immune function in mice. Here, we characterise in skeletal muscle. We found that mouse was expressed at low levels in healthy muscle but that its levels increased during hypertrophy or regeneration; in humans, was highly expressed in tissues from patients with various muscle diseases, such as in dystrophic muscle and alveolar rhabdomyosarcoma.

Limbal epithelial stem cell activity and corneal epithelial cell cycle parameters in adult and aging mice.

Limbal epithelial stem cells (LESCs) are believed to be responsible for corneal epithelial maintenance and repair after injury, but their activity has never been properly quantified in aging or wounded eyes. In this study, labelling with thymidine analogues, 5-iodo-2'-deoxyuridine (IdU), 5-chloro-2'-deoxyuridine (CldU) and 5-ethynyl-2'-deoxyuridine (EdU), was used to estimate cell-cycle time of the corneal and limbal epithelia in wild-type eyes, comparing aging (12 months) and young adult (8 week) mice. In C57BL/6 mice, cells cycled significantly faster in the central corneal epithelium of aging eyes (3.

Vascular anomalies of the upper limb.

Vascular anomalies are common in the upper extremities, but there continues to be a relative paucity of information about them in publications dealing with surgery in the hands and upper limbs. The wide spectrum of pathology and an inconsistent use of terminology make vascular anomalies susceptible to incorrect diagnosis and as a result, to misdirected management. This article aims to provide an update on vascular anomalies relevant to the upper limbs, focusing on significant advances in pathogenesis and genetics, classification systems, diagnosis and treatment.

Analysis of the relationship between the KRAS G12V oncogene and the Hippo effector YAP1 in embryonal rhabdomyosarcoma.

Persistent hyperactivity of the Hippo effector YAP in activated satellite cells is sufficient to cause embryonal rhabdomyosarcoma (ERMS) in mice. In humans, YAP is abundant and nuclear in the majority of ERMS cases, and high YAP expression is associated with poor survival. However, YAP1 is rarely mutated in human ERMS.

The teratogenic effects of thalidomide on limbs.

Thalidomide remains notorious as a result of the damage it caused to children born to mothers who used it to treat morning sickness between 1957 and 1961. The re-emergence of the drug to treat a range of conditions including erythema nodosum leprosum (a complication of leprosy) has led to a new generation of thalidomide damaged children being born in Brazil. Although thalidomide affects most of the developing tissues and organs of the body, the damage to the limbs is striking.

Lens-regulated retinoic acid signalling controls expansion of the developing eye.

Absence of the developing lens results in severe eye defects, including substantial reductions in eye size. How the lens controls eye expansion and the underlying signalling pathways are very poorly defined. We identified , a gene crucial for retinoic acid synthesis during embryogenesis, as a key factor downregulated in the peripheral retina (presumptive ciliary body region) of lens-removed embryonic chicken eyes prior to overt reductions in eye size.

Expression analysis of limb element markers during mouse embryonic development.

Background: While data regarding expression of limb element and tissue markers during normal mouse limb development exist, few studies show expression patterns in upper and lower limbs throughout key limb development stages. A comparison to normal developmental events is essential when analyzing development of the limb in mutant mice models.

Results: Expression patterns of the joint marker Gdf5, tendon and ligament marker Scleraxis, early muscle marker MyoD1, and blood vessel marker Cadherin5 (Cdh5) are presented during the most active phases of embryonic mouse limb patterning.

The syndrome of proximal femur, fibula, and midline metatarsal long bone deficiencies.

Human lower limb congenital long bone deficiencies cluster primarily at three distinct skeletal locations. Proximal femoral and fibular reductions are known phenomena. In contrast, midline metatarsal deficiencies have been misrepresented as lateral.