Cold Spring Harbor perspectives in biology最新文献

The RAS oncogene is a crucial driver of a number of cancers. The GTPase it encodes links growth factor receptors with signaling pathways that control cell proliferation. Activating mutations in RAS deregulate these pathways, promoting tumor progression. In this excerpt from his forthcoming book on the history of cancer research, Joe Lipsick looks back at the discovery of RAS and the subsequent work that revealed its mechanism of action-from the early work on rat sarcoma viruses to biochemical studies that revealed the role of GTP-GDP exchange and work that characterized downstream MAP kinase cascades in a variety of different organisms.

Mendel conducted his studies on the transmission of genetic elements from one generation to the next using pea varieties commercially available at that time. He presented segregation data for seven character differences in detail. The molecular basis of five of these character differences is known, round versus wrinkled seeds, yellow versus green cotyledons, green versus yellow pods, colored versus uncolored seed coats, and tall versus short stems. Wrinkled peas available in Mendel's time resulted from a transposon insertion in the gene encoding starch-branching enzyme I. Allelic variants in the gene encoding magnesium dechelatase are known to condition pea seeds with green cotyledons, while yellow pods are conditioned by a deletion variant that disrupts chlorophyll synthase gene function. Cultivars with unpigmented seed coats and white flowers are explained by a splicing defect in a gene encoding a basic helix-loop-helix transcription factor. Short cultivars used by Mendel were deficient in bioactive forms of the phytohormone gibberellin because they carried a missense allele of a gene encoding gibberellin 3-oxidase. The allelic diversity of the pea genes Mendel studied and the genetic heterogeneity of corresponding traits are discussed below. The identification of two of Mendel's genes remains to be formally confirmed.

How tissue architecture and function emerge during development and what facilitates their resilience and homeostatic dynamics during adulthood is a fundamental question in biology. Biological tissue barriers such as the skin epidermis have evolved strategies that integrate dynamic cellular turnover with high resilience against mechanical and chemical stresses. Interestingly, both dynamic and resilient functions are generated by a defined set of molecular and cell-scale processes, including adhesion and cytoskeletal remodeling, cell shape changes, cell division, and cell movement. These traits are coordinated in space and time with dynamic changes in cell fates and cell mechanics that are generated by contractile and adhesive forces. In this review, we discuss how studies on epidermal morphogenesis and homeostasis have contributed to our understanding of the dynamic interplay between biochemical and mechanical signals during tissue morphogenesis and homeostasis, and how the material properties of tissues dictate how cells respond to these active stresses, thereby linking cell-scale behaviors to tissue- and organismal-scale changes.

Oxidative stress is associated with increasing telomere shortening and telomere dysfunction, as well as with numerous pathologies in humans, including inflammatory diseases and cancer. Critically short and dysfunctional telomeres lose their ability to protect chromosome ends, which triggers irreversible growth arrest, termed senescence, or genomic instability. Telomeres are highly sensitive to damage from reactive oxygen species, which increase under conditions of oxidative stress. This work covers the evidence that oxidative damage to telomeric DNA alters telomere maintenance by various mechanisms and describes the DNA repair pathways important for preserving telomere function under oxidative stress conditions.

Whereas Mendelian genetics is an important research program in the life sciences, its school version is problematic. On the one hand, it contains stereotypical representations of Gregor Mendel's work that misrepresent his findings and the historical context. This deprives students from gaining an authentic picture of how science is done. On the other hand, what most students end up learning in schools are extremely simplistic accounts of heredity, whereby alleles directly control traits and phenotypes, and thus exclusively depend on which allele an individual has. Such oversimplifications of Mendelian genetics as those that we still teach in schools were exploited by ideologues in the beginning of the twentieth century to provide the presumed "scientific" basis for eugenics. This paper addresses these problems of the school version of Mendelian genetics, which I call "naive" Mendelian genetics. It also proposes a shift in school education from teaching how the science of genetics is done using model systems to teaching the complexities of development through which heredity is materialized.

Neural development must construct neural circuits that can perform the computations necessary for survival. However, many theoretical models of development do not explicitly address the computational goals of the resulting networks, or computations that evolve in time. Recurrent neural networks (RNNs) have recently come to prominence as both models of neural circuit computation and building blocks of powerful artificial intelligence systems. Here, we review progress in using RNNs for understanding how developmental processes lead to effective computations, and how abnormal development disrupts these computations.

Human telomeres play critical roles in protecting chromosome ends and preserving genomic integrity. Telomerase, essential for maintaining telomere length and cellular replicative capacity, is only expressed in a small subset of human cells: stem and progenitor populations. Conversely, most somatic cells' telomeres shorten with each cell division; this shortening provides a potent tumor suppressor mechanism. Thus, telomerase regulation shapes not only cellular life span and differentiation, but also the regenerative capacity and long-term integrity of tissues. Here, we review the current understanding of telomere length control and telomerase regulation in humans, from molecular interactions at chromosome ends to the tissue-specific variation of telomere length dynamics, drawing insight from pluripotent and adult stem cell populations, as well as telomerase dysregulation in cancer and telomere biology disorders.

Efforts to determine how telomeres solve the end-protection problem led to the discovery of shelterin, a conserved six-subunit protein complex that specifically binds to the long arrays of telomeric TTAGGG repeats at vertebrate chromosome ends. The mechanisms by which shelterin prevents telomeres from being detected as sites of DNA damage and how shelterin prevents inappropriate DNA repair pathways are now largely known. More recently, shelterin has emerged as a central player in solving the second major problem at telomeres: how to complete the duplication of telomeric DNA. This end-replication problem results from the inability of the canonical DNA replication machinery to maintain the DNA at chromosome ends. Shelterin solves this problem by recruiting two enzymes that can replenish the lost telomeric repeats: telomerase and CST-Polα/primase. How shelterin accomplishes these critical tasks is reviewed here.

As cells migrate inside the body, they encounter various biochemical and physical cues that provide them with directional guidance. In the past 20 years or so, there has been a significant shift in the effort to understand how physical factors contribute to cellular behaviors. Nevertheless, much of the research has been focused on the interactions between migrating cells and the extracellular matrix in vitro as these are simpler and more accessible models, while neglecting the importance of the cellular environment, which often requires in vivo model systems. With the development of new technology along with the appropriate choice of model organisms, the interesting topic of cell-on-cell interaction during migration is beginning to unravel. In this review, we will take a deep dive into some of the recent results that demonstrate how the biophysics of the cellular environment can impact cell migration, with a strong focus on the use of in vivo model systems, naming the Drosophila border cells, the Xenopus cephalic neural crest, and the zebrafish posterior lateral line primordium.

Blood vessels are critical to deliver oxygen and nutrients to tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier (BBB), which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and protects the neural tissue from toxins and pathogens, and alterations of this barrier are important components of the pathogenesis and progression of various neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the brain endothelial cells (ECs) that form the walls of the blood vessels. These properties are regulated by interactions between different vascular, perivascular, immune, and neural cells. Understanding how these cell populations interact to regulate barrier properties is essential for understanding how the brain functions in both health and disease contexts.