Salivary gland development in Drosophila melanogaster

The Drosophila salivary gland is proving to be an excellent experimental system for understanding how cells commit to specific developmental programs and, once committed, how cells implement such decisions. Through genetic studies, the factors that determine where salivary glands will form, the number of cells committed to a salivary gland fate, and the distinction between the two major cell types (secretory cells and duct cells) have been discovered. Within the next few years, we will learn the molecular details of the interactions among the salivary gland regulators and salivary gland target genes. We will also learn how the early-expressed salivary gland genes coordinate their activities to mediate the morphogenetic movements required to form the salivary gland and the changes in cell physiology required for high secretory activity.     

Organ formation in Drosophila: specification and morphogenesis of the salivary gland

The Drosophila salivary gland has emerged as an outstanding model system for the process of organ formation. Many of the component steps, from initial regional specification through cell specialization and morphogenesis, are known and many of the genes required for these different processes have been identified. The salivary gland is a relatively simple organ; the entire gland comprises of only two major cell types, which derive from a single contiguous primordium. Salivary cells cease dividing once they are specified, and organ growth is achieved simply by an increase in size of individual cells, thus eliminating concerns about the potential unequal distribution of determinants during mitosis. Drosophila salivary glands form by the same cellular mechanisms as organs in higher organisms, including regulated cell shape changes, cell intercalation and directed cell migration. Thus, learning how these events are coordinated for tissue morphogenesis in an organism for which the genetic and molecular tools are unsurpassed should provide excellent paradigms for dissecting related processes in the more intricate organs of more complicated species.     

Interactions between developing nerves and salivary glands

Our aim is to provide a summary of the field of salivary gland development and regeneration from the perspective of what is known about the function of nerves during these processes. The primary function of adult salivary glands is to produce and secrete saliva. Neuronal control of adult salivary gland function has been a focus of research ever since Pavlov’s seminal experiments on salivation in dogs. Less is known about salivary gland innervation during development and how the developing nerves influence gland organogenesis and regeneration. Here, we will review what is known about the communication between the autonomic nervous system and the epithelium of the salivary glands during organogenesis. An important emerging theme is the instructive role of the nervous system on the epithelial stem/progenitor cells during development as well as regeneration after damage. We will provide a brief overview of the neuroanatomy of the salivary glands and discuss recent literature that begins to integrate neurobiology with epithelial organogenesis, which may provide paradigms for exploring these interactions in other organ systems.     

Salivary gland determination in Drosophila: a salivary-specific, fork head enhancer integrates spatial pattern and allows fork head autoregulation

In the early Drosophila embryo, a system of coordinates is laid down by segmentation genes and dorsoventral patterning genes. Subsequently, these coordinates must be interpreted to define particular tissues and organs. To begin understanding this process for a single organ, we have studied how one of the first salivary gland genes, fork head (fkh), is turned on in the primordium of this organ, the salivary placode. A placode-specific fkh enhancer was identified 10 kb from the coding sequence. Dissection of this enhancer showed that the apparently homogeneous placode is actually composed of at least four overlapping domains. These domains appear to be developmentally important because they predict the order of salivary invagination, are evolutionarily conserved, and are regulated by patterning genes that are important for salivary development. Three dorsoventral domains are defined by EGF receptor (EGFR) signaling, while stripes located at the anterior and posterior edges of the placode depend on wingless signaling. Further analysis identified sites in the enhancer that respond either positively to the primary activator of salivary gland genes, SEX COMBS REDUCED (SCR), or negatively to EGFR signaling. These results show that fkh integrates spatial pattern directly, without reference to other early salivary gland genes. In addition, we identified a binding site for FKH protein that appears to act in fkh autoregulation, keeping the gene active after SCR has disappeared from the placode. This autoregulation may explain how the salivary gland maintains its identity after the organ is established. Although the fkh enhancer integrates information needed to define the salivary placode, and although fkh mutants have the most extreme effects on salivary gland development thus far described, we argue that fkh is not a selector gene for salivary gland development and that there is no master, salivary gland selector gene. Instead, several genes independently sense spatial information and cooperate to define the salivary placode.     

Rac function in epithelial tube morphogenesis

Epithelial cell migration and morphogenesis require dynamic remodeling of the actin cytoskeleton and cell-cell adhesion complexes. Numerous studies in cell culture and in model organisms have demonstrated the small GTPase Rac to be a critical regulator of these processes; however, little is known about Rac function in the morphogenic movements that drive epithelial tube formation. Here, we use the embryonic salivary glands of Drosophila to understand the role of Rac in epithelial tube morphogenesis. We show that inhibition of Rac function, either through loss of function mutations or dominant-negative mutations, disrupts salivary gland invagination and posterior migration. In contrast, constitutive activation of Rac induces motile behavior and subsequent cell death. We further show that Rac regulation of salivary gland morphogenesis occurs through modulation of cell-cell adhesion mediated by the E-cadherin/beta-catenin complex and that shibire, the Drosophila homolog of dynamin, functions downstream of Rac in regulating beta-catenin localization during gland morphogenesis. Our results demonstrate that regulation of cadherin-based adherens junctions by Rac is critical for salivary gland morphogenesis and that this regulation occurs through dynamin-mediated endocytosis.     

Fork head and Sage maintain a uniform and patent salivary gland lumen through regulation of two downstream target genes, PH4alphaSG1 and PH4alphaSG2

(Fkh) is required to block salivary gland apoptosis, internalize salivary gland precursors, prevent expression of duct genes in secretory cells and maintain expression of CrebA, which is required for elevated secretory function. Here, we characterize two new Fkh-dependent genes: PH4alphaSG1 and PH4alphaSG2. We show through in vitro DNA-binding studies and in vivo expression assays that Fkh cooperates with the salivary gland-specific bHLH protein Sage to directly regulate expression of PH4alphaSG2, as well as sage itself, and to indirectly regulate expression of PH4alphaSG1. PH4alphaSG1 and PH4alphaSG2 encode alpha-subunits of resident ER enzymes that hydroxylate prolines in collagen and other secreted proteins. We demonstrate that salivary gland secretions are altered in embryos missing function of PH4alphaSG1 and PH4alphaSG2; secretory content is reduced and shows increased electron density by TEM. Interestingly, the altered secretory content results in regions of tube dilation and constriction, with intermittent tube closure. The regulation studies and phenotypic characterization of PH4alphaSG1 and PH4alphaSG2 link Fkh, which initiates tube formation, to the maintenance of an open and uniformly sized secretory tube.     

Wasp, the Drosophila Wiskott-Aldrich syndrome gene homologue, is required for cell fate decisions mediated by Notch signaling

Wiskott-Aldrich syndrome proteins, encoded by the Wiskott-Aldrich syndrome gene family, bridge signal transduction pathways and the microfilament-based cytoskeleton. Mutations in the Drosophila homologue, Wasp (Wsp), reveal an essential requirement for this gene in implementation of cell fate decisions during adult and embryonic sensory organ development. Phenotypic analysis of Wsp mutant animals demonstrates a bias towards neuronal differentiation, at the expense of other cell types, resulting from improper execution of the program of asymmetric cell divisions which underlie sensory organ development. Generation of two similar daughter cells after division of the sensory organ precursor cell constitutes a prominent defect in the Wsp sensory organ lineage. The asymmetric segregation of key elements such as Numb is unaffected during this division, despite the misassignment of cell fates. The requirement for Wsp extends to additional cell fate decisions in lineages of the embryonic central nervous system and mesoderm. The nature of the Wsp mutant phenotypes, coupled with genetic interaction studies, identifies an essential role for Wsp in lineage decisions mediated by the Notch signaling pathway.     

Downstream of homeotic genes: in the heart of Hox function

A functional organ is constituted of diverse cell types. Each one occupies a distinct position and is associated to specific morphological and physiological functions. The identification of the genetic programs controlling these elaborated and highly precise features of organogenesis is crucial to understand how a mature organ works under normal conditions, and how pathologies can develop. Recently, a number of studies have reported a critical role for Hox genes in one example of organogenesis: cardiogenesis in Drosophila. Beyond the interest in understanding the molecular basis of functional cardiogenesis, this system might provide a model for proposing new paradigms of how Hox genes achieve their action throughout development.     

FoxA转录因子在肝脏发育中的研究进展

FoxA蛋白是一类DNA结合区具有翼状螺旋结构的转录因子,已发现其三名成员FoxAl、FoxA2和FoxA3在哺乳动物胚胎期的器官形成、成体时期的新陈代谢和内环境稳定中起着重要作用。肝脏发育FoxA亚家族成员起着关键调控作用,在肝向命运决定中扮演“先锋因子”的角色。该文对FoxA转录因子在肝脏发育中的调控作用进行了小结,综述了近年来的最新研究成果。     

Notch signaling in hematopoiesis and lymphopoiesis: lessons from Drosophila

The evolutionarily conserved Notch signaling pathway regulates a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal life. It is involved in embryonic organogenesis as well as in the maintenance of homeostasis of self-renewing systems. In this article, we review the role of Notch signaling in the hematopoietic system with particular emphasis on lymphocyte development and highlight the similarities in Notch function between Drosophila and mammalian differentiation processes. Recent studies indicating that aberrant NOTCH signaling is frequently linked to the induction of T leukemia in humans will also be discussed.     

Pax基因家族在果蝇发育过程中的调控作用

Pax是一个在进化上相当保守的基因家族, 它们编码的产物是一组极为重要的转录调控因子, 并存在于从果蝇到人类的各种生物体中, 参与细胞内信号传导通路的调控, 在胚胎发育过程中对细胞分化、更新、凋亡起重要的调控作用, 影响器官和组织的形成。果蝇中已发现10个Pax基因家族成员, 它们对果蝇胚胎发育及成虫组织器官的分化有非常重要的调控作用。文章结合最新的研究进展, 就果蝇中Pax基因的结构、表达模式和主要功能做一简要综述。