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  • Review Article
  • Published:

Organogenesis

Molecular Mechanisms Of Tubulogenesis

Key Points

  • As organisms increased in size and complexity, tubular systems evolved to transport substances into and out of the body with maximum efficiency.

  • Although the final structure of tubular organs is markedly different, common elements of cell behaviour underlie their formation. A fundamental feature of all tubular organs is that they are made up of cells that have apical–basal polarity. The cells have a clearly defined apical membrane facing the central lumen and a basal surface that is attached to a layer of extracellular matrix, both of which are connected by specialized intercellular junctions. Acquiring this polarity is a defining event in tubulogenesis.

  • Different strategies for elaborating tubes are discussed, as well as mechanisms for elongating tubes, connecting them together, and remodelling tubular networks during development. The special role of tips cells in controlling the elongation of tubes is also discussed.

  • Genetic analysis of tubular systems in model organisms has given important insights into the basic mechanisms that underlie their formation and remodelling. Examples are given from Drosophila (salivary gland and tracheal system), Caenorhabditis elegans (excretory cells), zebrafish (gut and vascular system) and mouse (lung, mammary gland and neural tube).

  • In vitro culture systems have also given insights into the basic mechanisms of tubulogenesis, including the role of intracellular signalling through receptor tyrosine kinases in directing apical polarity, cytoskeletal organization and formation of cell contacts.

  • In the future, we need to know more about the mechanisms that have evolved to co-ordinate the interdependent growth and differentiation of the different components of tubular organs, such as the epithelial tubes, the surrounding smooth muscle cells and the vascular system. These mechanisms presumably increase the efficiency of tubular systems and their response to physiological needs.

Abstract

As organisms have evolved in size and complexity, tubular systems have developed to enable the efficient transport of substances into and out of tissues. These tubular systems are generated using strategies that are based on common elements of cell behaviour, including cell polarization, tube migration to target sites, cell-fate diversification and localization of specialized cells to different regions of the tube system. Using examples from both invertebrate and vertebrate systems, this review highlights progress in understanding these basic principles and briefly discusses the possible evolution of strategies to regulate the morphogenesis of tubular systems.

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Figure 1: Acquisition of apical–basal polarity is essential for lumen formation.
Figure 2: Basic strategies for generating tubular systems.
Figure 3: Central lumen formation in a cord of cells.
Figure 4: Vasculogenesis and angiogenesis in the vertebrate embryo.
Figure 5: Lumen formation during anastomosis between two tubes.

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Acknowledgements

We thank M. Fishman and S. Childs for making their manuscript available before publication, D. Andrew for stimulating discussion and our colleagues M. Weaver, S. Hanks, Y. Li, R. Zent and T. Zhong for comments on the manuscript. Work in our laboratories is supported by the Howard Hughes Medical Institute and the National Institutes of Health. B.L.M.H. is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to Brigid L. M. Hogan.

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DATABASES

FlyBase

RhoA

Abdominal-B

Branchless

Breathless

crumbs

Dpp

fkh

Fog

Huckebein

raw

ribbon

Scr

Semaphorin II

Short Stop

Shotgun

Sp1

teashirt

zipper

LocusLink

angiopoietin-1

Cdc42

ephrin B2

Fgf10

hepatocyte growth factor

Jam

Lef1

Msx1

Msx2

neuropilin-1

p120

Pdgfa

PLCγ

Pthrp

Roundabout

Sonic hedgehog

Stat3

TTF2

Vegfa

Wormbase

exc-5

sma-1

OMIM

faciogenital dysplasia

spina bifida

Glossary

PRIMARY TRACHEAL SACS

The precursors to the Drosophila trachea that form a sack-like structure, before any branching occurs.

TIGHT JUNCTION

A connection between individual cells in epithelium that forms a diffusion barrier between the two surfaces of an epithelium.

ADHERENS JUNCTION

A cell–cell and cell–extracellular-matrix adhesion complex that is composed of integrins and cadherins that are attached to cytoplasmic actin filaments.

DESMOSOME

A patch-like adhesive intercellular junction that is linked to intermediate filaments — cytoskeletal components. They are found in vertebrate tissues, especially in tissues undergoing mechanical stress.

IMAGINAL DISC

An epithelial sheet that gives rise to the external adult structures of insects, such as the wing, eye and antennae.

PLACODE

A disc-shaped group of columnar epithelial cells that detaches from an epithelial sheet to give rise to an organ.

EXCRETORY CELL

A cell in the nematode Caenorhabditis elegans that allows waste excretion. The intracellular lumen of an excretory cell is known as the ventral canal.

CENTRAL CANAL

A fluid-filled channel in the centre of the single excretory cell.

PARASEGMENT

Segmentation genes pattern parasegments, regions of the Drosophila embryo that contain the posterior part of a hemisegment and the anterior part of its neighbor. Mesodermal thickenings and ectodermal grooves demarcate parasegment borders.

DORSAL CLOSURE

An event in Drosophila embryogenesis when the epidermis migrates as a sheet towards the dorsal midline. The sides of the sheet meet at the midline, enclosing the embryo.

DELAMINATION

The detachment of cells from an epithelial sheet.

AGENESIS

Failure of a tissue to develop.

ANGIOBLAST

Precursor of endothelial cells in blood-vessel wall.

MIDLINE

The anterior–posterior line bisecting the dorsal side of the vertebrate embryo.

HYPOCHORD

A thin rod-like structure of cells that runs along the length of the Xenopus embryo below the notochord, and may be involved in inducing dorsal aorta formation.

DORSAL AORTA

The main artery that runs to the embryonic heart.

SUBMANDIBULAR GLAND

Salivary gland located underneath the jaw.

DESMOSOME

Specialized cell–cell junction between epithelial cells that is connected to intermediate filaments, one of the cytoskeletal element types.

PYCNOTIC

The appearance of a nucleus in a cell that is undergoing apoptosis or programmed cell death as it shrinks and the chromosomes condense.

SEMAPHORINS

A family of secreted or transmembrane molecules that all contain at least one semaphorin repeat in their extracellular domain, which repel migrating cells and growth cones in the nervous system and other tissues.

CARDINAL VEINS

The main veins carrying blood out of the embryonic heart.

ANASTOMOSES

Plural of anastomosis, the site at which two blind-ended tubes join together to form a single tube.

ANGIOPOIETINS

Secreted factors that bind to the Tie2 receptor and that modulate vascular permeability and remodelling.

HEMISEGMENTAL BOUNDARY

A boundary between two hemisegments, the portions of a segment between the ventral and dorsal midlines, along the anterior/posterior axis.

PLAKIN

A family of large (250–600 kDa) proteins that contain a central rod domain, and sites for binding F-actin, microtubules, and/or intermediate filaments.

SOMITE

Mesodermal balls of cells adjacent to the neural tube that will differentiate into the muscle, vertebrae and dermis.

DORSAL LONGITUDINAL ANASTOMOTIC VESSEL

(DLAV). The vein that runs parallel to the dorsal aorta in the zebrafish, and is connected to the dorsal aorta by the intersegmental veins.

FENESTRATION

A round window, 63–68 nm in diameter, that cuts through subsets of endothelial cells. They are covered by a membraneous diaphragm that contains a fibrillar meshwork.

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Hogan, B., Kolodziej, P. Molecular Mechanisms Of Tubulogenesis. Nat Rev Genet 3, 513–523 (2002). https://doi.org/10.1038/nrg840

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