Annual Review of Cell and Developmental Biology - Volume 20, 2004

Cell polarity, as reflected by polarized growth and organelle segregation during cell division in yeast, appears to follow a simple hierarchy. On the basis of physical cues from previous cell cycles or stochastic processes, yeast cells select a site for bud emergence that also defines the axis of cell division. Once polarity is established, rho protein-based signal pathways set up a polarized cytoskeleton by activating localized formins to nucleate and assemble polarized actin cables. These serve as tracks for the transport of secretory vesicles, the segregation of the trans Golgi network, the vacuole, peroxisomes, endoplasmic reticulum, mRNAs for cell fate determination, and microtubules that orient the nucleus in preparation for mitosis, all by myosin-Vs encoded by the MYO2 and MYO4 genes. Most of the proteins participating in these processes in yeast are conserved throughout the kingdoms of life, so the emerging models are likely to be generally applicable. Indeed, several parallels to cellular organization in animals are evident.

During brain development, neurons migrate great distances from proliferative zones to generate the cortical gray matter. A series of studies has identified genes that are critical for migration and targeting of neurons to specific brain regions. These genes encode three basic groups of proteins and produce three distinct phenotypes. The first group encodes cytoskeletal molecules and produces graded and dosage-dependent effects, with a significant amount of functional redundancy. This group also appears to play important roles during the initiation and ongoing progression of neuronal movement. The second group encodes signaling molecules for which homozygous mutations lead to an inverted cortex. In addition, this group is responsible for movement of neurons through anatomic boundaries to specific cortical layers. The third group encodes enzymatic regulators of glycosylation and appears to delineate where neuronal migration will arrest. There is significant cross-talk among these different groups of molecules, suggesting possible points of pathway convergence.

The nervous system of higher organisms exhibits extraordinary cellular diversity owing to complex spatial and temporal patterning mechanisms. The role of spatial patterning in generating neuronal diversity is well known; here we discuss how neural progenitors change over time to contribute to cell diversity within the central nervous system (CNS). We focus on five model systems: the vertebrate retina, cortex, hindbrain, spinal cord, and Drosophila neuroblasts. For each, we address the following questions: Do multipotent progenitors generate different neuronal cell types in an invariant order? Do changes in progenitor-intrinsic factors or progenitor-extrinsic signals regulate temporal identity (i.e., the sequence of neuronal cell types produced)? What is the mechanism that regulates temporal identity transitions; i.e., what triggers the switch from one temporal identity to the next? By applying the same criteria to analyze each model system, we try to highlight common themes, point out unique attributes of each system, and identify directions for future research.

Myosin motor proteins use the energy derived from ATP hydrolysis to move cargo along actin tracks. Myosin VI, unlike almost all other myosins, moves toward the minus end of actin filaments and functions in a variety of intracellular processes such as vesicular membrane traffic, cell migration, and mitosis. These diverse roles of myosin VI are mediated by interaction with a number of different binding partners present in multi-protein complexes. Myosin VI can work in vitro as a processive dimeric motor and as a nonprocessive monomeric motor, each with a large working stroke. The possibility that both monomeric and dimeric forms of myosin VI operate in the cell may represent an important regulatory mechanism for controlling the multiple steps in transport pathways where nonprocessive and processive motors are required.

The problem of organelle size control can be addressed most simply by considering cellular structures that are linear, so that their size can be defined by a single parameter: length. We compare existing studies on several linear biological structures including prokaryotic flagella and flagellar hooks, eukaryotic flagella, sarcomere thin filaments, and microvilli. In some cases, existing evidence strongly supports the idea that length control involves a molecular ruler, in which the size of the overall structure is compared with the size of an individual molecule. In other cases, length control is likely to involve a steady-state balance of assembly and disassembly, in which one or the other rate is inherently length dependent. The lessons learned from size control in linear structures should be applicable to organelles with more complex three-dimensional structures.

The study of the epithelium of the adult mammalian intestine touches upon many modern aspects of biology. The epithelium is in a constant dialogue with the underlying mesenchyme to control stem cell activity, proliferation in transit-amplifying compartments, lineage commitment, terminal differentiation and, ultimately, cell death. There are spatially distinct compartments dedicated to each of these events. The Wnt, TGF-beta, BMP, Notch, and Par polarity pathways are the major players in homeostatic control of the adult epithelium. Several hereditary cancer syndromes deregulate these same signaling cascades through mutational (in)activation. Moreover, these mutations often also occur in sporadic tumors. Thus symmetry exists between the roles that these signaling pathways play in physiology and in cancer of the intestine. This is particularly evident for the Wnt/APC pathway, for which the mammalian intestine has become one of the most-studied paradigms. Here, we integrate recent knowledge of the molecular inner workings of the prototype signaling cascades with their specific roles in intestinal epithelial homeostasis and in neoplastic transformation of the epithelium.

The principles underlying regeneration in planarians have been explored for over 100 years through surgical manipulations and cellular observations. Planarian regeneration involves the generation of new tissue at the wound site via cell proliferation (blastema formation), and the remodeling of pre-existing tissues to restore symmetry and proportion (morphallaxis). Because blastemas do not replace all tissues following most types of injuries, both blastema formation and morphallaxis are needed for complete regeneration. Here we discuss a proliferative cell population, the neoblasts, that is central to the regenerative capacities of planarians. Neoblasts may be a totipotent stem-cell population capable of generating essentially every cell type in the adult animal, including themselves. The population properties of the neoblasts and their descendants still await careful elucidation. We identify the types of structures produced by blastemas on a variety of wound surfaces, the principles guiding the reorganization of pre-existing tissues, and the manner in which scale and cell number proportions between body regions are restored during regeneration.

Dynactin is a multisubunit protein complex that is required for most, if not all, types of cytoplasmic dynein activity in eukaryotes. Dynactin binds dynein directly and allows the motor to traverse the microtubule lattice over long distances. A single dynactin subunit, p150^Glued, is sufficient for both activities, yet dynactin contains several other subunits that are organized into an elaborate structure. It is currently believed that the bulk of the dynactin structure participates in interactions with a wide range of cellular structures, many of which are cargoes of the dynein motor. Genetic studies verify the importance of all elements of dynactin structure to its function. Although dynein can bind some membranous cargoes independently of dynactin, establishment of a fully functional dynein-cargo link appears to depend on dynactin. In this review, I summarize what is presently known about dynactin structure, the cellular structures with which it associates, and the intermolecular interactions that underlie and regulate binding. Although the molecular details of dynactin's interactions with membranous organelles and other molecules are complex, the framework provided here is intended to distill what is presently known and to be of use to dynactin specialists and beginners alike.

Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.

Gap junctions contain hydrophilic membrane channels that allow direct communication between neighboring cells through the diffusion of ions, metabolites, and small cell signaling molecules. They are made up of a hexameric array of polypeptides encoded by the connexin multi-gene family. Cell-cell communication mediated by connexins is crucial to various cellular functions, including the regulation of cell growth, differentiation, and development. Mutations in connexin genes have been linked to a variety of human diseases, including cardiovascular anomalies, peripheral neuropathy, deafness, skin disorders, and cataracts. In addition to their coupling function, recent studies suggest that connexin proteins may also mediate signaling. This could involve interactions with other protein partners that may play a role not only in connexin assembly, trafficking, gating and turnover, but also in the coordinate regulation of cell-cell communication with cell adhesion and cell motility. The integration of these cell functions is likely to be important in the role of gap junctions in development and disease.

Considerable evidence shows that lateral inhomogeneities in lipid composition and physical properties exist in biological membranes. These membrane lipid domains are proposed to play important roles in processes such as signal transduction and membrane traffic. However, there is not at present an adequate description of the nature of these lipid domains in terms of their size, abundance, composition, or dynamics. We discuss the current analyses of the properties and function of membrane domains in cells and compare their properties with chemically simpler model membrane systems that can be understood in greater detail.

Microtubules are dynamic polymers required for many aspects of eukaryotic cell function. The interphase microtubule network is essential for intracellular transport, organization, and cell polarization, whereas the mitotic spindle is required for chromosome segregation and cell division. Studies in different areas such as cell migration, mitosis, and asymmetric cell division have shown that Ran, Rho, and heterotrimeric G proteins regulate many aspects of microtubule functions. This review surveys how G protein–signaling coordinates microtubule polymerization and organization with specific cellular activities.