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Retinoic acid receptors (RARα/β/γ) and retinoid X receptors (RXRα/β/γ) are nuclear transcription factors that mediate the effects of retinoic acid (RA) on gene expression.13 Studies have shown that RA (a physiological active metabolite of vitamin A) is necessary for the proper embryonic development and morphogenesis of neural tubes. However, it may not be involved in neural tube closure.14 Both RARs and RXRs form heterodimers that bind to RA-response elements (RAREs) in the promoters of target genes to regulate their transcription.13 Suppression of RARs due to vitamin A deficiency has been shown to contribute to embryonic skeleton hypoplasia.15 Selective activation of RXRs has been shown to exhibit antidiabetic effects and play a role in the activation of insulin-sensitizing genes.16 Mitogen-activated protein kinases (MAPKs) play a major role in growth, differentiation, and development, and their activation has been shown as a determinant of the fate of embryonic organogenesis when exposed to insult.17 Previous work from our laboratory has shown that RA affects MAPK signaling via PI3K (Phosphatidylinositol 3-kinases) and Rac1 during neuronal cell differentiation.18 In addition, diabetes inhibits the activation of Rac1 and reduces the expression of neuronal markers in rat embryonic day 16 (E16) cortical neurons.19




Skeleton For Genesis 9.rar



Abstract:In metazoans, Hox genes are key drivers of morphogenesis. In chordates, they play important roles in patterning the antero-posterior (A-P) axis. A crucial aspect of their role in axial patterning is their collinear expression, a process thought to be linked to their response to major signaling pathways such as retinoic acid (RA) signaling. The amplification of Hox genes following major events of genome evolution can contribute to morphological diversity. In vertebrates, RA acts as a key regulator of the gene regulatory network (GRN) underlying hindbrain segmentation, which includes Hox genes. This review investigates how the RA signaling machinery has evolved and diversified and discusses its connection to the hindbrain GRN in relation to diversity. Using non-chordate and chordate deuterostome models, we explore aspects of ancient programs of axial patterning in an attempt to retrace the evolution of the vertebrate hindbrain GRN. In addition, we investigate how the RA signaling machinery has evolved in vertebrates and highlight key examples of regulatory diversification that may have influenced the GRN for hindbrain segmentation. Finally, we describe the value of using lamprey as a model for the early-diverged jawless vertebrate group, to investigate the elaboration of A-P patterning mechanisms in the vertebrate lineage.Keywords: hindbrain; segmentation; A-P patterning; gene regulatory networks (GRNs); Hox genes; retinoic acid (RA); RA signaling; vertebrate evolution; lamprey; RA synthesis and degradation; Cyp26 and Aldh1a2 enzymes


Osteogenesis imperfecta (OI) is a rare disease affecting the connective tissue and is characterized by extremely fragile bones that break or fracture easily (brittle bones). The abnormal growth of bones is often referred to as a bone dysplasia. The specific symptoms and physical findings associated with OI vary greatly from person to person. The severity of OI also varies greatly, even among individuals in the same family. OI may be a mild disorder or result in severe complications.


In all types of osteogenesis imperfecta, symptoms vary greatly from one individual to the next, even within the same type and the same family. Some affected individuals may not experience any bone fractures or only a few. Other affected individuals experience multiple fractures. The age of onset of fractures varies from person to person. OI is a collagen related disease, and as such, the arrangement and integrity of teeth (dentition), lung function, heart (cardiac) function, muscle strength and ligament flexibility may be affected as well.


Osteogenesis type I is the most common and usually the mildest form of OI. In most people, it is characterized by multiple bone fractures, usually occurring during childhood through puberty. A child with type I OI may fracture early in life with minimal trauma (falling from a standing position or when being pulled up by a caregiver), whereas others may fracture later on when participating in higher intensity physical activity. Fractures during the newborn (neonatal) period are rare. The frequency of fractures usually declines after puberty. Repeated fractures may result in slight malformation of the bones of the arms and legs (e.g., bowing of the tibia and femur).


Additional symptoms associated with OI type I include loose (hyper extensible) joints and low muscle tone (hypotonia). This may result in a predisposition to joint dislocations and ligament sprains. Some patients have skin that bruises easily. Brittle teeth (dentinogenesis) are uncommon in type I OI.


OI type II is the most severe type of osteogenesis imperfecta. Affected infants often experience life-threatening complications at birth or shortly after. Infants with OI type II have low birth weight, abnormally short arms and legs and blue sclera. In addition, affected infants have extremely fragile bones and numerous fractures present at birth. The ribs and long bones of the legs are often malformed.


Infants with OI type III may have a slight blue discoloration to the whites of the eyes at birth. In most patients, the bluish tinge fades during the first year of life. Affected infants often have a triangular facial appearance due to an abnormally prominent forehead (frontal bossing) and a small jaw (micrognathia). Hearing loss may develop during the first decade. Dentinogenesis imperfecta may also be present. Type III patients may develop pulmonary problems secondary to abnormal lung tissue and chest wall abnormalities.


Individuals with OI type IV may have a triangular facial appearance. In most patients, the sclera are normal or pale blue during infancy. As an infant ages, the pale blue discoloration of the sclera fades. Affected individuals may also experience hearing impairment and dentinogenesis imperfecta.


Osteogenesis Imperfecta types I through IV are caused by mutations in the COL1A1 or COL1A2 genes. These genes carry instructions for the production of type 1 collagen. Collagen is the major protein of bone and connective tissue including the skin, tendons and sclera. The collagen protein is made up of three strands of proteins (two alpha 1 strands and one alpha 2 strand) that wind together in a helical fashion. These helical molecules then pack side by side to form characteristic bands that are linked together. This structure gives collagen enormous tensile strength. When a mutation occurs, the collagen that the mutated gene produces may be faulty or insufficient. In type I, the gene mutation results in a normal collagen protein, but only one-half of the normal amount is produced. Types II through IV are the result of mutations that affect the structure of the collagen protein. The precise location and type of mutation determines the severity of the resulting disease. The non-collagen types of OI (types V-XXI) are caused by mutations in genes that code for other proteins that play a pivotal role in the production of normal collagen.


Over 80 percent of the mutations that cause osteogenesis imperfecta are inherited in an autosomal dominant pattern. That means that an affected individual has only one copy of the mutated gene. The mutated gene dominates the normal gene such that the affected individual forms only abnormal collagen (as in types II-V) or only makes half the normal amount of collagen (as in type I). Autosomal dominant mutations can be passed down from parent to child. This autosomal dominant transmission accounts for about 60 percent of new diagnoses of OI cases each year. In another 20-30 percent of new cases annually, OI is caused by a spontaneous autosomal dominant mutation in the affected individual. This new dominant mutation can then be passed down to future generations. The risk of transmitting the autosomal dominant disorder from affected parent to offspring is 50 percent for each pregnancy and the risk is the same for males and females.


Osteogenesis imperfecta affects males and females in equal numbers. The incidence of cases recognizable at birth is 1:10-20,000. More mild types that are only recognized later in life occur at about the same incidence. It is estimated that 20,000 to 50,000 individuals in the United States have OI.


A diagnosis of osteogenesis imperfecta is made based upon a detailed patient and family history and a thorough clinical evaluation to identify characteristic signs and symptoms. Genetic testing is performed to detect the known genetic mutations that cause OI.


Apronen H, Makitie O, Waltimo-Siren J. Association between joint hypermobility, scoliosis, and cranial base anomalies in paediatric osteogenesis imperfecta patients: a retrospective cross-sectional study. BMC Musculoskelet Disord. 2014 Dec 13;15:428.


Martinez-Glez V, Valencia M, Caparros-Martin JA, et al. Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta. Hum Mutat. 2012;33: 343-350.


Coordinated development of muscles, tendons, and their attachment sites ensures emergence of functional musculoskeletal units that are adapted to diverse anatomical demands among different species. How these different tissues are patterned and functionally assembled during embryogenesis is poorly understood. Here, we investigated the morphogenesis of extraocular muscles (EOMs), an evolutionary conserved cranial muscle group that is crucial for the coordinated movement of the eyeballs and for visual acuity. By means of lineage analysis, we redefined the cellular origins of periocular connective tissues interacting with the EOMs, which do not arise exclusively from neural crest mesenchyme as previously thought. Using 3D imaging approaches, we established an integrative blueprint for the EOM functional unit. By doing so, we identified a developmental time window in which individual EOMs emerge from a unique muscle anlage and establish insertions in the sclera, which sets these muscles apart from classical muscle-to-bone type of insertions. Further, we demonstrate that the eyeballs are a source of diffusible all-trans retinoic acid (ATRA) that allow their targeting by the EOMs in a temporal and dose-dependent manner. Using genetically modified mice and inhibitor treatments, we find that endogenous local variations in the concentration of retinoids contribute to the establishment of tendon condensations and attachment sites that precede the initiation of muscle patterning. Collectively, our results highlight how global and site-specific programs are deployed for the assembly of muscle functional units with precise definition of muscle shapes and topographical wiring of their tendon attachments. 041b061a72


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