Loss of Planar Cell Polarity Effector Fuzzy Causes Renal Hypoplasia by Disrupting Several Signaling Pathways

In vertebrates, the planar cell polarity (PCP) pathway regulates tissue morphogenesis during organogenesis, including the kidney. Mutations in human PCP effector proteins have been associated with severe syndromic ciliopathies. Importantly, renal hypoplasia has been reported in some patients. However, the developmental disturbance that causes renal hypoplasia is unknown. Here, we describe the early onset of profound renal hypoplasia in mice homozygous for null mutation of the PCP effector gene, Fuzzy. We found that this phenotype is caused by defective branching morphogenesis of the ureteric bud (UB) in the absence of defects in nephron progenitor specification or in early steps of nephrogenesis. By using various experimental approaches, we show that the loss of Fuzzy affects multiple signaling pathways. Specifically, we found mild involvement of GDNF/c-Ret pathway that drives UB branching. We noted the deficient expression of molecules belonging to the Bmp, Fgf and Shh pathways. Analysis of the primary cilia in the UB structures revealed a significant decrease in ciliary length. We conclude that renal hypoplasia in the mouse Fuzzy mutants is caused by defective UB branching associated with dysregulation of ciliary and non-ciliary signaling pathways. Our work suggests a PCP effector-dependent pathogenetic mechanism that contributes to renal hypoplasia in mice and humans.

NKL Homeobox Genes NKX2-3 and NKX2-4 Deregulate Megakaryocytic-Erythroid Cell Differentiation in AML

NKL homeobox genes encode transcription factors that impact normal development and hematopoietic malignancies if deregulated. Recently, we established an NKL-code that describes the physiological expression pattern of eleven NKL homeobox genes in the course of hematopoiesis, allowing evaluation of aberrantly activated NKL genes in leukemia/lymphoma. Here, we identify ectopic expression of NKL homeobox gene NKX2-4 in an erythroblastic acute myeloid leukemia (AML) cell line OCI-M2 and describe investigation of its activating factors and target genes. Comparative expression profiling data of AML cell lines revealed in OCI-M2 an aberrantly activated program for endothelial development including master factor ETV2 and the additional endothelial signature genes HEY1, IRF6, and SOX7. Corresponding siRNA-mediated knockdown experiments showed their role in activating NKX2-4 expression. Furthermore, the ETV2 locus at 19p13 was genomically amplified, possibly underlying its aberrant expression. Target gene analyses of NKX2-4 revealed activated ETV2, HEY1, and SIX5 and suppressed FLI1. Comparative expression profiling analysis of public datasets for AML patients and primary megakaryocyte–erythroid progenitor cells showed conspicuous similarities to NKX2-4 activating factors and the target genes we identified, supporting the clinical relevance of our findings and developmental disturbance by NKX2-4. Finally, identification and target gene analysis of aberrantly expressed NKX2-3 in AML patients and a megakaryoblastic AML cell line ELF-153 showed activation of FLI1, contrasting with OCI-M2. FLI1 encodes a master factor for myelopoiesis, driving megakaryocytic differentiation and suppressing erythroid differentiation, thus representing a basic developmental target of these homeo-oncogenes. Taken together, we have identified aberrantly activated NKL homeobox genes NKX2-3 and NKX2-4 in AML, deregulating genes involved in megakaryocytic and erythroid differentiation processes, and thereby contributing to the formation of specific AML subtypes.

A Neurodevelopment Approach for a Transitional Model of Early Onset Schizophrenia

In the last decades, the conceptualization of schizophrenia has dramatically changed, moving from a neurodegenerative process occurring in early adult life to a neurodevelopmental disorder starting be-fore birth, showing a variety of premorbid and prodromal symptoms and, in relatively few cases, evolving in the full-blown psychotic syndrome. High rates of co-occurring different neurodevelopmental disorders such as Autism spectrum disorder and ADHD, predating the onset of SCZ, and neurobio-logical underpinning with significant similarities, support the notion of a pan-developmental disturbance consisting of impairments in neuromotor, receptive language, social and cognitive development. Con-sidering that many SCZ risk factors may be similar to symptoms of other neurodevelopmental psychi-atric disorders, transition processes from child & adolescent to adult systems of care should include both high risk people as well as subject with other neurodevelopmental psychiatric disorders with different levels of severity. This descriptive mini-review discuss the need of innovative clinical approaches, re-considering specific diagnostic categories, stimulating a careful analysis of risk factors and promoting the appropriate use of new and safer medications.

Collimated Microbeam Reveals that the Proportion of Non-Damaged Cells in Irradiated Blastoderm Determines the Success of Development in Medaka (Oryzias latipes) Embryos

It has been widely accepted that prenatal exposure to ionizing radiation (IR) can affect embryonic and fetal development in mammals, depending on dose and gestational age of the exposure, however, the precise machinery underlying the IR-induced disturbance of embryonic development is still remained elusive. In this study, we examined the effects of gamma-ray irradiation on blastula embryos of medaka and found transient delay of brain development even when they hatched normally with low dose irradiation (2 and 5 Gy). In contrast, irradiation of higher dose of gamma-rays (10 Gy) killed the embryos with malformations before hatching. We then conducted targeted irradiation of blastoderm with a collimated carbon-ion microbeam. When a part (about 4, 10 and 25%) of blastoderm cells were injured by lethal dose (50 Gy) of carbon-ion microbeam irradiation, loss of about 10% or less of blastoderm cells induced only the transient delay of brain development and the embryos hatched normally, whereas embryos with about 25% of their blastoderm cells were irradiated stopped development at neurula stage and died. These findings strongly suggest that the developmental disturbance in the IR irradiated embryos is determined by the proportion of severely injured cells in the blastoderm.

DENTAL FLUOROSIS AND PERIODONTAL DISEASE: AN OVERVIEW

Aim: The aim of this review is to discuss various effects of fluoride on hard and soft tissues of the periodontium and its importance in human life. Background : Fluoride is an essential element for life and is one of the trace elements normally present in the body. It is abundant in the environment and the main source of fluoride to humans is drinking water. Fluoride gets accumulated in hard tissues of the body and has been known to play an important role in mineralization of bone and teeth. The behaviourof fluoride ions in the human organism can be regarded as that of double-edged sword. In small amounts, it is known to have beneficial effects on dental health. On the other hand, excessive chronic intakes can result in adverse effects including the development of dental fluorosis in children and/or skeletal fluorosis in both children and adults. Although effect of fluoride on caries has been discussed in painstaking details through various studies but the effect of fluorosis on the periodontium yet remains in shadow. Review Results : Dental fluorosis is a developmental disturbance of dental enamel, caused by successive exposures to high concentrations of fluoride during tooth development, leading to enamel with lower mineral content and increased porosity. Even after continuing with the age old logic of structural changes that take place in mottled enamel it can be said with scientific plausibility that this factor of surface roughness can or must influence some of the variables in this multifactorial disease of periodontitis. This surface roughness is conducive for the bacteria to survive as well as make it difficult for scaling and root planing in fluorosed teeth. This could also jeopardize the effectiveness of the regular oral hygiene procedures. Conclusion : Dental fluorosis is not only a cosmetic problem that impairs social well-being but also affects the oral health related quality of life. Fluorosis continues to be an important problem, both for the affected individuals and for public health. More and more areas are being discovered regularly that are affected by fluorosis in different parts of the country. But ultimate solution for this fluoride menace remains to be the principal of Precaution is better than cure. Clinical Significance : Considering the role of fluorosis on hard and soft tissues and all the risk factors of periodontitis, fluorosis can be recommended strongly as an environmental risk factor for periodontitis. To be defined as one of the etiological (environmental) agent of periodontal disease requires further research studies with greater sample size from varying areas globally.

Unique Presentation of “U Shaped” Impacted maxillary Central Incisor with Surgical and Pedodontic perspectives: A Case report

Background Dilaceration, a developmental disturbance, is thought to be due to trauma leading to change in the position of the calcified portion of the tooth and the tooth is formed at an angle. Such an injury to a permanent tooth, resulting in dilacerations, often follows traumatic injury to the primary predecessor. A study by Patiletal, on Indian population reported the prevalence of very rare developmental dental anomalies and dilaceration was found to be only about 0.5% in prevalence. Case details A 9 year old male reported to the department of paediatric dentistry with complaint of missing central incisor in maxillary left arch. Radiographic examination revealed impacted maxillary left incisor with very unique and unusual extreme curve in root of same tooth giving it a characteristic U morphology. As the patient reported in mixed dentition stage, both the surgical, prosthodontic and pedodontic perspectives were kept in mind before planning for the treatment. Surgical removal was planned as it was not possible to save and place the tooth in the arch. Although surgical removal was challenging due to extreme curve and highly placed position of tooth, surgical removal was done successfully with roots and crown broken in two sections in spite of proper care during extraction procedure. Edentulous space was replaced with groper’s appliance considering mixed dentition stage of the patient after successful healing as per the pedodontic perspectives. Conclusion U shaped presentation of single rooted tooth is a one of the rarest findings. In children with age of interception, treatment should be planned wisely taking into consideration surgical, prosthodontic and pedodontic perspectives together. Key Words U shaped root, dilaceration, impacted tooth, surgical and pedodontic perspectives

Case report of a geminated premolar and hypodontia

This case report describes the diagnosis and treatment of a non-syndromic unilateral geminated second premolar complicated by hypodontia of three second premolars. Gemination is defined as a developmental disturbance of the shape of teeth and is usually recognized as a partial cleavage of a single tooth germ resulting in one root and one pulp space with two partially or totally separated crowns. Hypodontia is defined as the developmental absence of one or more teeth, excluding the third molars. Geminations of maxillary second premolars are rarely reported. These dental anomalies can cause local malocclusion manifesting as crowding or spacing. CPD/Clinical Relevance: Diagnosis of dental anomalies such as gemination can be difficult. This paper discusses the diagnosis and management of one such case which involved CBCT.

Developmental Disturbance of a Maxillary Permanent Lateral Incisor Following Trauma at the Age of 16 Months: A 6-Year Follow-Up

A 3 year and 8 months old Chinese boy was referred for a consultation regarding his missing maxillary anterior teeth. He had a history of trauma to his primary maxillary anterior teeth due to a fall at the age of 16 months. Clinical examination of the patient indicated multiple carious lesions and inadequate oral hygiene. Radiographic examination revealed intrusion of the primary left lateral incisor, with evidence of damage to the permanent tooth germ. Subsequently, the patient was followed-up for almost six years during which his permanent maxillary left lateral incisor erupted exhibiting an unusual morphology. Clinically enamel hypoplasia and radiographically dens invaginatus were evident in affected tooth.