Annual Review of Cell and Developmental Biology - Volume 29, 2013

Body axis elongation and segmentation are major morphogenetic events that take place concomitantly during vertebrate embryonic development. Establishment of the final body plan requires tight coordination between these two key processes. In this review, we detail the cellular and molecular as well as the physical processes underlying body axis formation and patterning. We discuss how formation of the anterior region of the body axis differs from that of the posterior region. We describe the developmental mechanism of segmentation and the regulation of body length and segment numbers. We focus mainly on the chicken embryo as a model system. Its accessibility and relatively flat structure allow high-quality time-lapse imaging experiments, which makes it one of the reference models used to study morphogenesis. Additionally, we illustrate conservation and divergence of specific developmental mechanisms by discussing findings in other major embryonic model systems, such as mice, frogs, and zebrafish.

Morphogenesis is the remarkable process by which cells self-assemble into complex tissues and organs that exhibit specialized form and function during embryological development. Many of the genes and chemical cues that mediate tissue and organ formation have been identified; however, these signals alone are not sufficient to explain how tissues and organs are constructed that exhibit their unique material properties and three-dimensional forms. Here, we review work that has revealed the central role that physical forces and extracellular matrix mechanics play in the control of cell fate switching, pattern formation, and tissue development in the embryo and how these same mechanical signals contribute to tissue homeostasis and developmental control throughout adult life.

Mitogen-activated protein kinases (MAPKs) are ancient signal transducers well characterized as mediators of inflammation and neoplastic transformation. Recent work has expanded our understanding of their developmental functions, particularly in the regulation of bone mass via control of osteoblast differentiation. Here, we review the functions of MAPK pathways in osteoblasts, including a consideration of MAPK substrates. In particular, MAPKs function to regulate the key transcriptional mediators of osteoblast differentiation, with ERK and p38 MAPKs phosphorylating RUNX2, the master regulator of osteoblast differentiation. ERK also activates RSK2, which in turn phosphorylates ATF4, a transcriptional regulator of late-stage osteoblast synthetic functions. The MAP3Ks and MAP2Ks upstream of MAPKs have also been investigated, and significant differences have been found in the wiring of MAPK pathways in osteoblasts relative to other tissues. Thus, the investigation of MAPKs in osteoblasts has both revealed critical mechanisms for the maintenance of bone mass and added to our understanding of how the individual components of MAPK pathways function in concert in a complex in vivo system.

The pancreas is an essential organ for proper nutrient metabolism and has both endocrine and exocrine function. In the past two decades, knowledge of how the pancreas develops during embryogenesis has significantly increased, largely from developmental studies in model organisms. Specifically, the molecular basis of pancreatic lineage decisions and cell differentiation is well studied. Still not well understood are the mechanisms governing three-dimensional morphogenesis of the organ. Strategies to derive transplantable β-cells in vitro for diabetes treatment have benefited from the accumulated knowledge of pancreas development. In this review, we provide an overview of the current understanding of pancreatic lineage determination and organogenesis, and we examine future implications of these findings for treatment of diabetes mellitus through cell replacement.

Adult animals rely on populations of stem cells to ensure organ function throughout their lifetime. Stem cells are governed by signals from stem cell niches, and much is known about how single niches promote stemness and direct stem cell behavior. However, most organs contain a multitude of stem cell–niche units, which are often distributed across the entire expanse of the tissue. Beyond the biology of individual stem cell–niche interactions, the next challenge is to uncover the tissue-level processes that orchestrate spatial control of stem-based renewal, repair, and remodeling throughout a whole organ. Here we examine what is known about higher order mechanisms for interniche coordination in epithelial organs, whose simple geometry offers a promising entry point for understanding the regulation of niche number, distribution, and activity. We also consider the potential existence of stem cell territories and how tissue architecture may influence niche coordination.

Many organs respond to physiological challenges by changing tissue size or composition. Such changes may originate from tissue-specific stem cells and their supportive environment (niche). The endocrine system is a major effector and conveyor of physiological changes and as such could alter stem cell behavior in various ways. In this review, we examine how hormones affect stem cell biology in four different organs: the ovary, intestine, hematopoietic system, and mammary gland. Hormones control every stage of stem cell life, including establishment, expansion, maintenance, and differentiation. The effects can be cell autonomous or non–cell autonomous through the niche. Moreover, a single hormone can affect different stem cells in different ways or affect the same stem cell differently at various developmental times. The vast complexity and diversity of stem cell responses to hormonal cues allow hormones to coordinate the body's reaction to physiological challenges.

Spermatogenesis originates from spermatogonial stem cells (SSCs). Development of the spermatogonial transplantation technique in 1994 provided the first functional assay to characterize SSCs. In 2000, glial cell line–derived neurotrophic factor was identified as a SSC self-renewal factor. This discovery not only provided a clue to understand SSC self-renewing mechanisms but also made it possible to derive germline stem (GS) cell cultures in 2003. In vitro culture of GS cells demonstrated their potential pluripotency and their utility in germline modification. However, in vivo SSC analyses have challenged the traditional concept of SSC self-renewal and have revealed their relationship with the microenvironment. An improved understanding of SSC self-renewal through functional assays promises to uncover fundamental principles of stem cell biology and will enable us to use these cells for applications in animal transgenesis and medicine.

Seeds are complex structures that unite diploid maternal tissues with filial tissues that may be haploid (gametophyte), diploid (embryo), or triploid (endosperm). Maternal tissues are predicted to favor smaller seeds than are favored by filial tissues, and filial genes of maternal origin are predicted to favor smaller seeds than are favored by filial genes of paternal origin. Consistent with these predictions, seed size is determined by an interplay between growth of maternal integuments, which limits seed size, and of filial endosperm, which promotes larger seeds. Within endosperm, genes of paternal origin favor delayed cellularization of endosperm and larger seeds, whereas genes of maternal origin favor early cellularization and smaller seeds. The ratio of maternal and paternal gene products in endosperm contributes to the failure of crosses between different ploidy levels of the same species and crosses between species. Maternally expressed small-interfering RNAs (siRNAs) are predicted to associate with growth-enhancing genes.

In the past decade, significant progress has been made in understanding both microRNA function and cellular pluripotency. Here we review the intersection of these two exciting fields. While microRNAs are not required for the establishment and maintenance of pluripotency in early development and cell culture, respectively, they are critically important in the regulation of the cell cycle structure of pluripotent stem cells as well as the silencing of the pluripotency program upon differentiation. Pluripotent cells, both in vivo and in vitro, dominantly express a single family of microRNAs, which can promote the reprogramming of a somatic cell back to a pluripotent state. Here, we review the known mechanisms by which these and other microRNAs regulate the different aspects of the pluripotent stem cell program in both mouse and human.

The repressive compartment of the nucleus is comprised primarily of telomeric and centromeric regions, the silent portion of ribosomal RNA genes, the majority of transposable element repeats, and facultatively repressed genes specific to different cell types. This compartment localizes into three main regions: the peripheral heterochromatin, perinucleolar heterochromatin, and pericentromeric heterochromatin. Both chromatin remodeling proteins and transcription of noncoding RNAs are involved in maintenance of repression in these compartments. Global reorganization of the repressive compartment occurs at each cell division, during early development, and during terminal differentiation. Differential action of chromatin remodeling complexes and boundary element looping activities are involved in mediating these organizational changes. We discuss the evidence that heterochromatin formation and compartmentalization may drive nuclear organization.

Axon regeneration after damage is widespread in the animal kingdom, and the nematode Caenorhabditis elegans has recently emerged as a tractable model in which to study the genetics and cell biology of axon regrowth in vivo. A key early step in axon regrowth is the conversion of part of a mature axon shaft into a growth cone–like structure, involving coordinated alterations in the microtubule, actin, and neurofilament systems. Recent attention has focused on microtubule dynamics as a determinant of axon-regrowth ability in several organisms. Live imaging studies have begun to reveal how the microtubule cytoskeleton is remodeled after axon injury, as well as the regulatory pathways involved. The dual leucine zipper kinase family of mixed-lineage kinases has emerged as a critical sensor of axon damage and plays a key role in regulating microtubule dynamics in the damaged axon.

The emergence of functional neuronal connectivity in the developing cerebral cortex depends on neuronal migration. This process enables appropriate positioning of neurons and the emergence of neuronal identity so that the correct patterns of functional synaptic connectivity between the right types and numbers of neurons can emerge. Delineating the complexities of neuronal migration is critical to our understanding of normal cerebral cortical formation and neurodevelopmental disorders resulting from neuronal migration defects. For the most part, the integrated cell biological basis of the complex behavior of oriented neuronal migration within the developing mammalian cerebral cortex remains an enigma. This review aims to analyze the integrative mechanisms that enable neurons to sense environmental guidance cues and translate them into oriented patterns of migration toward defined areas of the cerebral cortex. We discuss how signals emanating from different domains of neurons get integrated to control distinct aspects of migratory behavior and how different types of cortical neurons coordinate their migratory activities within the developing cerebral cortex to produce functionally critical laminar organization.

Nociception is the process whereby primary afferent nerve fibers of the somatosensory system detect noxious stimuli. Pungent irritants from pepper, mint, and mustard plants have served as powerful pharmacological tools for identifying molecules and mechanisms underlying this initial step of pain sensation. These natural products have revealed three members of the transient receptor potential (TRP) ion channel family—TRPV1, TRPM8, and TRPA1—as molecular detectors of thermal and chemical stimuli that activate sensory neurons to produce acute or persistent pain. Analysis of TRP channel function and expression has validated the existence of nociceptors as a specialized group of somatosensory neurons devoted to the detection of noxious stimuli. These studies are also providing insight into the coding logic of nociception and how specification of nociceptor subtypes underlies behavioral discrimination of noxious thermal, chemical, and mechanical stimuli. Biophysical and pharmacological characterization of these channels has provided the intellectual and technical foundation for developing new classes of analgesic drugs.

Synaptic connections between neurons form the basis for perception and behavior. Synapses are often clustered in space, forming stereotyped layers. In the retina and optic tectum, multiple such synaptic laminae are stacked on top of each other, giving rise to stratified neuropil regions in which each layer combines synapses responsive to a particular sensory feature. Recently, several cellular and molecular mechanisms that underlie the development of multilaminar arrays of synapses have been discovered. These mechanisms include neurite guidance and cell-cell recognition. Molecules of the Slit, Semaphorin, Netrin, and Hedgehog families, binding to their matching receptors, bring axons and dendrites into spatial register. These guidance cues may diffuse over short distances or bind to sheets of extracellular matrix, thus conditioning the local extracellular milieu, or are presented on the surface of cells bordering the future neuropil. In addition, mutual recognition of axons and dendrites through adhesion molecules with immunoglobulin domains ensures cell type–specific connections within a given layer. Thus, an elaborate genetic program assembles the parallel processing channels that underlie visual perception.

The microtubule (MT) cytoskeleton supports a broad range of cellular functions, from providing tracks for intracellular transport, to supporting movement of cilia and flagella, to segregating chromosomes in mitosis. These functions are facilitated by the organizational and dynamic plasticity of MT networks. An important class of enzymes that alters MT dynamics is the depolymerizing kinesin-like proteins, which use their catalytic activities to regulate MT end dynamics. In this review, we discuss four topics surrounding these MT-depolymerizing kinesins. We provide a historical overview of studies focused on these motors and discuss their phylogeny. In the second half, we discuss their enzymology and biophysics and give an overview of their known cellular functions. This discussion highlights the fact that MT-depolymerizing kinesins exhibit a diverse range of design principles, which in turn increases their functional versatility in cells.

Kinesin-2 was first purified as a heterotrimeric, anterograde, microtubule-based motor consisting of two distinct kinesin-related subunits and a novel associated protein (KAP) that is currently best known for its role in intraflagellar transport and ciliogenesis. Subsequent work, however, has revealed diversity in the oligomeric state of different kinesin-2 motors owing to the combinatorial heterodimerization of its subunits and the coexistence of both heterotrimeric and homodimeric kinesin-2 motors in some cells. Although the functional significance of the homo- versus heteromeric organization of kinesin-2 motor subunits and the role of KAP remain uncertain, functional studies suggest that cooperation between different types of kinesin-2 motors or between kinesin-2 and a member of a different motor family can generate diverse patterns of anterograde intracellular transport. Moreover, despite being restricted to ciliated eukaryotes, kinesin-2 motors are now known to drive diverse transport events outside cilia. Here, I review the organization, assembly, phylogeny, biological functions, and motility mechanism of this diverse family of intracellular transport motors.

Migration is a polarized cellular process that opposes a protrusive front edge to a retracting trailing edge. From the front to the rear, actin-mediated forces sequentially promote cell protrusion, adhesion, contraction, and retraction. Over the past decade, microtubules have revealed their pivotal role in cell migration. Through their roles in cell mechanics, intracellular trafficking, and signaling, microtubules participate in all essential events leading to cell migration. The front-rear polarization of microtubule functions relies on the asymmetric regulation of microtubule dynamics and stability; the asymmetric distribution of microtubule-associated protein complexes; and finally, the orientation of the microtubule network along the axis of migration. Microtubule network polarity controls the establishment and maintenance of the spatial and temporal coordination of migration events and is therefore the key to persistent directed migration. This review summarizes our current understanding of the functions of microtubules in persistent cell migration and of the migration-associated signals that promote microtubule network polarization.

A migrating cell is a molecular machine made of tens of thousands of short-lived and interacting parts. Understanding migration means understanding the self-organization of these parts into a system of functional units. This task is one of tackling complexity: First, the system integrates numerous chemical and mechanical component processes. Second, these processes are connected in feedback interactions and over a large range of spatial and temporal scales. Third, many processes are stochastic, which leads to heterogeneous migration behaviors. Early on in the research of cell migration it became evident that this complexity exceeds human intuition. Thus, the cell migration community has led the charge to build mathematical models that could integrate the diverse experimental observations and measurements in consistent frameworks, first in conceptual and more recently in molecularly explicit models. The main goal of this review is to sift through a series of important conceptual and explicit mathematical models of cell migration and to evaluate their contribution to the field in their ability to integrate critical experimental data.

Shape changes and topological remodeling of membranes are essential for the identity of organelles and membrane trafficking. Although all cellular membranes have common features, membranes of different organelles create unique environments that support specialized biological functions. The endoplasmic reticulum (ER) is a prime example of this specialization, as its lipid bilayer forms an interconnected system of cisternae, vesicles, and tubules, providing a highly compartmentalized structure for a multitude of biochemical processes. A variety of peripheral and integral membrane proteins that facilitate membrane curvature generation, fission, and/or fusion have been identified over the past two decades. Among these, the dynamin-related proteins (DRPs) have emerged as key players. Here, we review recent advances in our functional and molecular understanding of fusion DRPs, exemplified by atlastin, an ER-resident DRP that controls ER structure, function, and signaling.