Current Topics in Developmental Biology最新文献

In the vestibular inner ear, multiple hair-cell organs decompose head movements into angular or linear components with distinct planes of action, time course, frequencies, and amplitudes. The hair cell responses are transmitted to vestibular afferents and propagated to the brain, where the signals contribute to orientation and heading perception and drive reflexes that stabilize vision and posture during movement. Mammalian and other amniote vestibular epithelia feature two hair cell types (I and II) with distinctive afferent synaptic contacts (calyx and bouton) and transmission mechanisms (nonquantal versus quantal), and are organized into central and peripheral zones that generate afferent populations with fundamentally different encoding properties. In altricial rodents like mice, physiological differences between hair cells, afferents and zones emerge prenatally and develop over several postnatal weeks. The mouse utricle is a model system for investigating developmental differentiation of afferent signals by virtue of its highly organized epithelium, accessibility of immature stages, and genetic tractability. Physiological studies demonstrate that selective acquisition of low-voltage-activated potassium channels from the K_V1 (Kcna) and K_V7 (Kcnq) families profoundly shapes the maturing sensory signal at multiple stages: hair cell receptor potentials become faster, synaptic transmission from type I hair cells becomes nonquantal, and afferent spike patterns become more irregular. Targeted genetic manipulations coupled with behavioral assessments have revealed transcription factors that regulate the physiological differentiation of hair cell and afferent types. Developmental mechanisms to create new hair cells, hair bundles and functional synapses persist at low levels in mature vestibular epithelia, allowing some regeneration and repair to sustain transduction and transmission for years.

Animals perceiving light through visual pigments have evolved pathways for absorbing, transporting, and metabolizing the precursors essential for synthesis of their retinylidene chromophores. Over the past decades, our understanding of this metabolism has grown significantly. Through genetic manipulation, researchers gained insights into the metabolic complexity of the pathways mediating the flow of chromophore precursors throughout the body, and their enrichment within the eyes. This exploration has identified transport proteins and metabolizing enzymes for these essential lipids and has revealed some of the fundamental regulatory mechanisms governing this process. What emerges is a complex framework at play that maintains ocular retinoid homeostasis and functions. This review summarizes the recent advancements and highlights future research directions that may deepen our understanding of this complex metabolism.

Gamete membrane fusion in mammals brings the paternal genome into the cytoplasm of the egg. It also enables signals to pass from the sperm into the egg to trigger the completion of meiosis and the start of embryo development. The essential signal to activate development in all mammals studied, consists of a series of transient increases in the cytosolic Ca²⁺ concentration driven by cycles of InsP₃ production. This review focusses on the characteristics of these sperm-induced Ca²⁺ signals. I consider how some specific features of sperm-derived phospholipase C-zeta (PLCζ), along with the known properties of the type 1 InsP₃ receptor, provide a basis for understanding the mechanisms of the dynamic changes in Ca²⁺ observed in fertilizing eggs. I describe how the PLCζ targeting of cytoplasmic vesicles in the egg cytoplasm, that contain PI(4,5)P₂, is necessary to explain the rapid waves associated with the rising phase of each Ca²⁺ transient. I also discuss the importance of the repetitive Ca²⁺ rises for egg activation and the way mitochondrial ATP production may modulate Ca²⁺ release in eggs. Finally, I consider the role that a sperm-induced ATP increase may play in the egg activation process.

Oocytes, a uniquely pivotal cell population, play a central role in species continuity. In mammals, oogenesis involves distinct processes characterized by sequential rounds of selection, arrest, and activation to produce a limited number of mature eggs, fitting their high-survival yet high-cost fertility. During the embryonic phase, oocytes undergo intensive selection via cytoplasmic and organelle enrichment, accompanied by the onset and arrest of meiosis, thereby establishing primordial follicles (PFs) as a finite reproductive reserve. Subsequently, the majority of primary oocytes enter a dormant state and are gradually recruited through a process termed follicle activation, essential for maintaining orderly fertility. Following activation, oocytes undergo rapid growth, experiencing cycles of arrest and activation regulated by endocrine and paracrine signals, ultimately forming fertilizable eggs. Over the past two decades, advancements in genetically modified animal models, high-resolution imaging, and omics technologies have significantly enhanced our understanding of the cellular and molecular mechanisms that govern mammalian oogenesis. These advances offer profound insights into the regulatory mechanisms of mammalian reproduction and associated female infertility disorders. In this chapter, we provide an overview of current knowledge in mammalian oogenesis, with a particular emphasis on oocyte selection and activation in vivo.

All-trans RA (ATRA) is a small molecule derived from retinol (vitamin A) that directly controls gene expression at the transcriptional level by serving as a ligand for nuclear ATRA receptors. ATRA is produced by ATRA-generating enzymes that convert retinol to retinaldehyde (retinol dehydrogenase; RDH10) followed by conversion of retinaldehyde to ATRA (retinaldehyde dehydrogenase; ALDH1A1, ALDH1A2, or ALDH1A3). Determining what ATRA normally does during vertebrate development has been challenging as studies employing ATRA gain-of-function (RA treatment) often do not agree with genetic loss-of-function studies that remove ATRA via knockouts of ATRA-generating enzymes. In mouse embryos, ATRA is first generated at stage E7.5 by ATRA-generating enzymes whose genes are first expressed at that stage. This article focuses upon what ATRA normally does at early stages based upon these knockout studies. It has been observed that early-generated ATRA performs three essential functions: (1) activation of genes that control hindbrain and spinal cord patterning; (2) repression of Fgf8 in the heart field and caudal progenitors to provide an FGF8-free region in the trunk essential for somitogenesis, heart morphogenesis, and initiation of forelimb fields; and (3) actions that stimulate invagination of the optic vesicle to form the optic cup.

The active metabolite of vitamin A, all-trans-retinoic acid (atRA), is critical for maintenance of many cellular processes. Although the enzymes that can synthesize and clear atRA in mammals have been identified, their tissue and cell-type specific roles are still not fully established. Based on the plasma protein binding, tissue distribution and lipophilicity of atRA, atRA partitions extensively to lipid membranes and other neutral lipids in cells. As a consequence, free atRA concentrations in cells are expected to be exceedingly low. As such mechanisms must exist that allow sufficiently high atRA concentrations to occur for binding to retinoic acid receptor (RARs) and for RAR mediated signaling. Kinetic simulations suggest that cellular retinoic acid binding proteins (CRABPs) provide a cytosolic reservoir for atRA to allow high enough cytosolic concentrations that enable RAR signaling. Yet, the different CRABP family members CRABP1 and CRABP2 may serve different functions in this context. CRABP1 may reside in the cytosol as a member of a cytosolic signalosome and CRABP2 may bind atRA in the cytosol and localize to the nucleus. Both CRABPs appear to interact with the atRA-degrading cytochrome P450 (CYP) family 26 enzymes in the endoplasmic reticulum. These interactions, together with the expression levels of the CRABPs and CYP26s, likely modulate cellular atRA concentration gradients and tissue atRA concentrations in a tightly coordinated manner. This review provides a summary of the current knowledge of atRA distribution, metabolism and protein binding and how these characteristics may alter tissue atRA concentrations.

Nephron formation and patterning are driven by complex cell biology. Progenitors migrate, transition into epithelia, and generate an axial epithelial polarity with distinct transcriptional signatures, regulating virtually all physiologies of the maturing kidney post birth. Here we review current insights into mammalian nephrogenesis and discuss how the nephron forms and patterns along its proximal-distal axis during embryonic and fetal development. Genetic pathways that are necessary for this process are discussed and integrated into the cell biology and morphogenetic programs underpinning nephrogenesis. Together, these views outline a developmental blueprint for replicating nephron formation in vitro.

After ejaculation, mammalian spermatozoa are not capable of fertilizing a metaphase II-arrested egg. They require to undergo a series of biochemical and physiological processes collectively known as capacitation. In all these processes, the regulation of calcium ions fluxes plays essential roles and involves participation of many channels and transporters localized in the plasma membrane as well as in the membrane of intracellular organelles. In mammalian sperm, a fraction of these molecules has been proposed to contribute to mature sperm function. However, in many cases, the evidence for the presence of a given protein is based on the use of agonists and antagonists with more than one target. In this review, we will critically analyze the published evidence supporting the presence of these molecules in mammalian sperm with special emphasis to methods involving tandem mass spectrometry identification, electrophysiological evidence and controlled immunoassays.

Primary cilia are essential cellular organelles with pivotal roles in many signalling pathways. Here we provide an overview of the role of primary cilia within the kidney, starting with primary ciliary structure and key protein complexes. We then highlight the specialised functions of primary cilia, emphasising their role in a group of diseases known as renal ciliopathies. These conditions include forms of polycystic kidney disease, nephronophthisis, and other syndromic ciliopathies, such as Joubert syndrome and Bardet-Biedl syndrome. We explore models of renal ciliopathies, both in vitro and in vivo, shedding light on the molecular mechanisms underlying these diseases including Wnt and Hedgehog signalling pathways, inflammation, and cellular metabolism. Finally, we discuss therapeutic approaches, from current treatments to cutting-edge preclinical research and clinical trials.