SciCombinator

Discover the most talked about and latest scientific content & concepts.

Journal: Current opinion in cell biology

168

The generation of functional endodermal lineages, such as hepatocytes and pancreatic endocrine cells, from pluripotent stem cells (PSCs) remains a challenge. One strategy to enhance the purity, yield and maturity of endodermal derivatives is to expand endoderm committed stem or progenitor cell populations derived from PSCs before final differentiation. Recent studies have shown that this is in fact a viable option both for expanding pure populations of endodermal cells as well as for generating more mature derivative tissues, as highlighted in the case of pancreatic beta cells.

Concepts: Developmental biology, Stem cell, Stem cells, Cell biology, Pancreas, Progenitor cell, Multipotency, Pluripotency

27

Dosage compensation of X-linked gene products between the sexes in therians has culminated in the inactivation of one of the two X chromosomes in female cells. Over the years, the mouse has been the preferred animal model to study this X-chromosome inactivation (XCI) process in placental mammals (eutherians). Similar to the imprinted inactivation of the paternally inherited X chromosome (Xp) in marsupials (methatherians), the Xp is inactivated during early mouse development. In this eutherian model, cell derivatives of the primitive endoderm (PE) and trophectoderm (TE) will continue to display this imprinted form of XCI. Cells developing from the mouse epiblast will reactivate the Xp, and subsequently initiate XCI of either the Xp or the maternally inherited Xm, in a random manner. Examination of XCI in other eutherians and in metatherians, however, indicates clear differences in the form and timing of XCI. This review highlights and discusses imprinted and random XCI from such a comparative viewpoint.

Concepts: Gene, Chromosome, Mammal, X chromosome, X-inactivation, Eutheria, Metatheria, Theria

25

Glial fibrillary acidic protein (GFAP) is the hallmark intermediate filament (IF; also known as nanofilament) protein in astrocytes, a main type of glial cells in the central nervous system (CNS). Astrocytes have a range of control and homeostatic functions in health and disease. Astrocytes assume a reactive phenotype in acute CNS trauma, ischemia, and in neurodegenerative diseases. This coincides with an upregulation and rearrangement of the IFs, which form a highly complex system composed of GFAP (10 isoforms), vimentin, synemin, and nestin. We begin to unravel the function of the IF system of astrocytes and in this review we discuss its role as an important crisis-command center coordinating cell responses in situations connected to cellular stress, which is a central component of many neurological diseases.

Concepts: Central nervous system, Nervous system, Brain, Neurology, Intermediate filament, Glial fibrillary acidic protein

12

Mammalian genomes are organized and regulated through long-range chromatin interactions. Structural loops formed by CCCTC-binding factor (CTCF) and cohesin fold the genome into domains, while enhancers interact with promoters across vast genomic distances to regulate gene expression. Although genomics and fixed-cell imaging approaches help illuminate many aspects of chromatin interactions, temporal information is usually lost. Here, we discuss how 3D super-resolution live-cell imaging (SRLCI) can resolve open questions on the dynamic formation and dissolution of chromatin interactions. We discuss SRLCI experimental design, implementation strategies, and data interpretation and highlight associated pitfalls. We conclude that, while technically demanding, SRLCI approaches will likely emerge as a critical tool to dynamically probe 3D genome structure and function and to study enhancer-promoter interactions and chromatin looping.

8

The cell surface is a mechanobiological unit that encompasses the plasma membrane, its interacting proteins, and the complex underlying cytoskeleton. Recently, attention has been directed to the mechanics of the plasma membrane, and in particular membrane tension, which has been linked to diverse cellular processes such as cell migration and membrane trafficking. However, how tension across the plasma membrane is regulated and propagated is still not completely understood. Here, we review recent efforts to study the interplay between membrane tension and the cytoskeletal machinery and how they control cell form and function. We focus on factors that have been proposed to affect the propagation of membrane tension and as such could determine whether it can act as a global or local regulator of cell behavior. Finally, we discuss the limitations of the available tool kit as new approaches that reveal its dynamics in cells are needed to decipher how membrane tension regulates diverse cellular processes.

6

Autosomal dominant missense mutations that hyperactivate the leucine-rich repeat protein kinase-2 (LRRK2) are a common cause of inherited Parkinson's disease and therapeutic efficacy of LRRK2 inhibitors is being tested in clinical trials. In this review, we discuss the nuts and bolts of our current understanding of how the LRRK2 is misregulated by mutations and how pathway activity is affected by LRRK2 binding to membrane, microtubule filaments, and 14-3-3, as well as by upstream components such as Rab29 and VPS35. We discuss recent work that points toward a subset of Rab proteins comprising key physiological substrates that bind new sets of effectors, such as RILPL1/2, JIP3 and JIP4 after phosphorylation by LRRK2. We explore what is known about how LRRK2 regulates ciliogenesis, the endosomal-lysosomal system, immune responses and interplay with alpha-synuclein and tau and how this might be linked to Parkinson’s' disease.

4

From unicellular protists to the largest megafauna and flora, all eukaryotes depend upon the organelles and processes of the intracellular membrane trafficking system. Well-defined machinery selectively packages and delivers material between endomembrane organelles and imports and exports material from the cell surface. This process underlies intracellular compartmentalization and facilitates myriad processes that define eukaryotic biology. Membrane trafficking is a landmark in the origins of the eukaryotic cell and recent work has begun to unravel how the revolution in cellular structure occurred.

3

Subversion of genome integrity fuels cellular adaptation and is a prerequisite for organismal evolution, yet genomic lesions are also the harmful driving force of cancer and other age-related human diseases. Genome integrity maintenance is inherently linked to genome organization and nuclear architecture, which are substantially remodeled during the cell cycle. Here we discuss recent findings on how actively dividing cells cope with endogenous genomic lesions that occur frequently at repetitive, heterochromatic, and late replicating regions as byproducts of genome duplication. We discuss how such lesions, rather than being resolved immediately when they occur, are dealt with in subsequent cell cycle phases, and even after mitotic cell division, and how this in turn affects genome organization, stability, and function.

3

Nucleosomes, the basic structures used to package genetic information into chromatin, are subject to a diverse array of chemical modifications. A large number of these marks serve as interaction hubs for many nuclear proteins and provide critical structural features for protein recruitment. Dynamic deposition and removal of chromatin modifications by regulatory proteins ensure their correct deposition to the genome, which is essential for DNA replication, transcription, chromatin compaction, or DNA damage repair. The spatiotemporal regulation and maintenance of chromatin marks relies on coordinated activities of writer, eraser, and reader enzymes and often depends on complex multicomponent regulatory circuits. In recent years, the field has made enormous advances in uncovering the mechanisms that regulate chromatin modifications. Here, we discuss well-established and emerging concepts in chromatin biology ranging from cooperativity and multivalent interactions to regulatory feedback loops and increased local concentration of chromatin-modifying enzymes.

3

Morphogenesis of multicellular systems is governed by precise spatiotemporal regulation of biochemical reactions and mechanical forces which together with environmental conditions determine the development of complex organisms. Current efforts in the field aim at decoding the system-level principles underlying the regulation of developmental processes. Toward this goal, optogenetics, the science of regulation of protein function with light, is emerging as a powerful new tool to quantitatively perturb protein function in vivo with unprecedented precision in space and time. In this review, we provide an overview of how optogenetics is helping to address system-level questions of multicellular morphogenesis and discuss future directions.