Morphogenesis

in our understanding of how feather buds develop in The exquisitely beautiful form of a developing embryo periodic patterns in the ectoderm of the chick embryo is the result of a coordination between the driving forces (Crowe et al., 1998; Jung et al., 1998; Noramly and Morof morphogenesis and the processes of cell growth, gan, 1998; Viallet et al., 1998). The insights that have proliferation, differentiation, and death. Morphogenesis come from studies on limbs and feathers, as well as is responsible for bringing cell populations together for simple organs in Drosophila such the tracheal system new inductive interactions and for building complex, (Krasnow, 1997) and the dorsal respiratory appendages three-dimensional structures such as hearts, limbs, of the egg (Wasserman and Freeman, 1998), are proving lungs, and eyes out of simple epithelial sheets and mesvery useful for understanding a more complex variation enchymal cell masses. Research over the past two deof the budding theme, typically refered to as “branching cades has elucidated many of the genetic pathways morphogenesis.” This process, in which a tree-like orunderlying cell division, cell fate determination, and difgan is generated by a reiterated combination of bud ferentiation, and has shown them to be evolutionarily outgrowth, elongation of a stem, and subdivision of terconserved. A major challenge now is to explore the minal buds, underlies the development of organs such possibility that there is also a conserved “morphogeas the mammalian pancreas, mammary gland, lung, netic code”—a set of rules common to processes that and kidney. In spite of the physiological importance of are used repeatedly in different combinations to make these organs, we are only just beginning to understand functional organs. These instructions fall into two catehow their early morphogenesis is controlled. Following gories. First, there are basic subroutines that define essome general observations, this review will focus on sentially mechanical operations such as the packaging one of these organs—the mammalian lung—as a model of cells into segments, the folding of epithelial sheets system. into tubes or cups, and the outgrowth of buds. Each of In vertebrates, budding invariably involves dynamic these modules utilizes sets of genes controlling properand reciprocal interactions between two cell populaties such as differential cell adhesion, cell motility, celltions—one mesenchymal and the other epithelial. For matrix interactions, and cytoskeletal organization. the purposes of this review, a primary bud is defined as The second category determines how these subroua knob-like cluster of progenitor cells located within tines are coordinated with cell proliferation and cell fate distinct boundaries that proliferate and move away from determination. This “project management” depends on the surface of a preexisting structure. A secondary bud signaling centers that arise in the organ primordia or develops on a stalk derived from another bud, while progenitor fields at positions initially determined by the branches arise by bifurcation of a terminal bud. Other primary embryonic axes. Each center is a group of cells distinct mechanisms for subdividing a bud also exist. that regulates the behavior of surrounding cells by proFor example, a terminal, ampulla-like bud may be ducing positive and negative intercellular signaling molcleaved into multiple lobules by the process of clefting, ecules. Evidence is beginning to accumulate that the involving the ingrowth of mesenchyme and the deposimajority of these signaling factors are proteins encoded tion of extracellular matrix. In some organs, such as the by a relatively small number of conserved multigene lung, budding, branching, and clefting each occur at families, in particular the Fgfs, Bmps, Hedgehogs, Wnts, different stages of development (see below), while in and Egfs. The diverse biological activities of individual organs such as the salivary gland, for example, clefting ligands are regulated by antagonists, activators, or postappears to predominate (Nakanishi and Ishii, 1989, for translational modifiers that control, for example, the review). range over which the protein can function or its halfSimple bud formation involves several stages. The life in the environment. In addition, the signaling genes first is initiation, in which the boundaries of a bud primorthemselves are often transcriptionally regulated by posidium, and the signaling centers within it, are gradually tive and/or negative feedback loops. An exciting pros-