Cloning,phylogeny, and regional expression of a Y5 receptor mRNA in the brain of the sea lamprey (Petromyzon marinus)

The NPY receptors known as Y receptors are classified into three subfamilies, Y1, Y2, and Y5, and are involved in different physiological functions. The Y5 receptor is the only member of the Y5 subfamily, and it is present in all vertebrate groups, except for teleosts. Both molecular and pharmacological studies show that Y5 receptor is highly conserved during vertebrate evolution. Furthermore, this receptor is widely expressed in the mammalian brain, including the hypothalamus, where it is thought to take part in feeding and homeostasis regulation. Lampreys belong to the agnathan lineage, and they are thought to have branched out between the two whole‐genome duplications that occurred in vertebrates. Therefore, they are in a key position for studies on the evolution of gene families in vertebrates. Here we report the cloning, phylogeny, and brain expression pattern of the sea lamprey Y5 receptor. In phylogenetic studies, the lamprey Y5 receptor clusters in a basal position, together with Y5 receptors of other vertebrates. The mRNA of this receptor is broadly expressed in the lamprey brain, being especially abundant in hypothalamic areas. Its expression pattern is roughly similar to that reported for other vertebrates and parallels the expression pattern of the Y1 receptor subtype previously described by our group, as it occurs in mammals. Altogether, these results confirm that a Y5 receptor is present in lampreys, thus being highly conserved during the evolution of vertebrates, and suggest that it is involved in many brain functions, the only known exception being teleosts. J. Comp. Neurol. 522:1132–1154, 2014. © 2013 Wiley Periodicals, Inc.     

神经细胞黏附分子L1在先天性巨结肠中的表达

目的：研究L1型神经细胞黏附分子（LICAM）基因在先天性巨结肠不同肠段的表达。方法：分别取16例先天性巨结肠惠儿狭窄段和正常段平滑肌组织，经处理后提取总RNA，应用逆转录多聚酶链反应（RT-PCR）扩增目的基因和看家基因片段，观察狭窄段和正常段的LICAM基因的表达，并与看家基因（β-aetin）在狭窄段和正常段的表迭作对比。结果：16例患者正常段LICAM和β-actin均有明显的表达，狭窄段β-actin亦有明显的表达，但LICAM均无表迭或弱表达。结论：先天性巨结肠患者狭窄段LICAM减少的原因可能是LICAM的mRNA的减少或缺如，并进一步引起病变段运动障碍和巨结肠发生。     

Disruption of actin‐binding domain‐containing Dystonin protein causes dystonia musculorum in mice

The Dystonin gene (Dst) is responsible for dystonia musculorum (dt), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. Dst‐a isoforms, which contain actin‐binding domains, are predominantly expressed in the nervous system. Although sensory neuron degeneration in the peripheral nervous system during the early postnatal stage is a well‐recognised phenotype in dt, the histological characteristics and neuronal circuits in the central nervous system responsible for motor symptoms remain unclear. To analyse the causative neuronal networks and roles of Dst isoforms, we generated novel multipurpose Dst gene trap mice, in which actin‐binding domain‐containing isoforms are disrupted. Homozygous mice showed typical dt phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (Dst^Gt) encodes a mutant Dystonin‐LacZ fusion protein, which is detectable by X‐gal (5‐bromo‐4‐chloro‐3‐indolyl‐β‐D‐galactoside) staining. We observed wide expression of the actin‐binding domain‐containing Dystonin isoforms in the central nervous system (CNS) and peripheral nervous system. This raised the possibility that not only secondary neuronal defects in the CNS subsequent to peripheral sensory degeneration but also cell‐autonomous defects in the CNS contribute to the motor symptoms. Expression analysis of immediate early genes revealed decreased neuronal activity in the cerebellar‐thalamo‐striatal pathway in the homozygous brain, implying the involvement of this pathway in the dt phenotype. These novel Dst^Gt mice showed that a loss‐of‐function mutation in the actin‐binding domain‐containing Dystonin isoforms led to typical dt phenotypes. Furthermore, this novel multipurpose Dst^Gt allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype.     

The diverse roles and multiple forms of focal adhesion kinase in brain

Although it was originally characterized as a constituent of focal adhesions in fibroblasts, focal adhesion kinase (FAK) is now considered to be not only a mediator of adhesion processes but also a crucial regulator of guidance and a modulator of gene expression. FAK is the main transducer of the integrin signaling required to stabilize the actin cytoskeleton. However, additional activities have been described over the years. In the brain, FAK deserves particular attention as it is found in various alternatively spliced forms – these distributed in multiple subcellular compartments or bound to multiple partners. Moreover, its signaling involves not only phosphorylation but also ubiquitination and proteolysis. Several experimental cell models demonstrate that FAK increases or decreases migration, participates in differentiation and contributes to plasticity events. In addition, this kinase is linked to cell survival in cancer and apoptosis. This review focuses on the diversity of events involving brain‐located forms of FAK.     

The Brazilian Founder Mutation TP53 p.R337H is Uncommon in Portuguese Women Diagnosed with Breast Cancer

Since the first studies reporting the TP53 p.R337H mutation as founder mutation in Southern and Southeastern Brazil, there has been controversy on its origin. Preliminary analysis of a small subset of Brazilian mutation carriers revealed that the haplotype incided on a Caucasian background. The vast majority of carriers identified today reside in Brazil or, if identified in other countries, are Brazilian immigrants. To our knowledge, the only two exceptions of carriers without a recognizable link with Brazil are two European families, from Portugal and Germany. Haplotype analysis in the Portuguese family revealed the same haplotype identified in Brazilian individuals, but in the German family, a distinct haplotype was found. Knowing that a significant proportion of women with breast cancer (BC) in Southern Brazil are p.R337H carriers, we analyzed p.R337H in a Portuguese cohort of women diagnosed with this disease. Median age at diagnosis among the first 573 patients tested was 60 years and 100 (17.4%) patients had been diagnosed at or under the age of 45 years. Mutation screening failed to identify the mutation in the 573 patients tested. These results are in contrast with the mutation frequency observed in a study including 815 BC‐affected women from Brazil, in which carrier frequencies of 12.1 and 5.1% in pre‐ and postmenopausal women were observed, respectively. These findings suggest that the Brazilian founder mutation p.R337H, the most frequent germline TP53 mutation reported to date, is not a common germline alteration in Portuguese women diagnosed with BC.