SnapShot: Branching Morphogenesis

A

Feather sheath

B

Pulp

Marginal plate

Barb ridge

Rachidial ridge

C

Marginal plate

Barb

BGZ

Barbs

Shh, Caspase

Barbule plate

Axial plate

Feather follicle opens by apoptosis to form a vane

D

E

Branches form Patterning branches through apoptosis

Barb

Rachis

Wnt3a gradient, Sprouty

Radial, bilateral symmetric, and asymmetric branching patterns form by modulating basal branching circuit

Pulp epithelium

Rachis

NCAM, Shh, caspase

BMP, Noggin, Sprouty, FGF

Barb ridge

Basal branch patterns form by differential cell death

Cell death, ECM remodeling, restored branching (serotonin, lactoferrin, STAT3, SMAD3)

Mammary gland

Feather

Terminal end buds (TEBs)

Secondary branching

MMP14 TIMP1 Nuclear actin FGFR2 MMP2 HSP90β Macrophages & eosinophils Patterned stromal collagen I TGF-β Laminin-1/BM

Regulating factors

Estrogen ER-α MMP3 HS2ST HGFR VDR MMP2 TIMP1 TGF-β

Regulating factors

Stem cells

A

D m1

α

C

Rachis zone

m2

A B

P

Barb forming zone

Bilateral symmetry

Dermal papilla

Follicle formation

Wnt3a β-catenin

Posterior

Wnt3a Shh BMP

Anterior

Regulating factors

β-catenin Wnt FGF BMP Shh TGFβ MMP2

Regulating factors

Branching by cell death

Adapted from Hennighausen and Robinson, 2005

Alveolar maturation and milk production (Prolactin, Oxytocin, SnoN, STAT5, Caveolin-1 SOCS1)

Budding and proliferation of alveoli (Progesterone, GATA3, STAT6, NDST1, Caveolin-1)

Invasion of epithelia into stromal fat pad

Ductal tree formation by iterative branching

Barb and rachis formation by a periodic invagination

Fat

Nipple

Terminal duct lobular units

Female breast after puberty

Fibroblastic stroma and fat

Anlage

Male and female newborn

Adult

Pregnancy

Lactation

Involution

Branching by invasion

Temporal spatial variation of signals

3a nt

DOI http://dx.doi.org/10.1016/j.cell.2014.08.019 Later W

Cell 158, August 28, 2014 ©2014 Elsevier Inc. Distal

nt

Puberty

Shaft

Lymph node

Progesterone PR-B Wnt4 MMP3 HS2ST HGFR MMP2 TIMP1 TGF-β End bud

st

Dermal papilla

Stem cells

Po

Vane

Regulating factors

Tertiary branching

m

Shaft formation

B

A

Barb forming zone

Radial symmetry

Proliferation BMP2 Sprouty FGF

Regulating factors

Ptc1 Proliferation TIMP2 Keratinization

Barb plate

Shh Apoptosis MMP2

Marginal plate

FGF10 Sprouty Noggin

Regulating factors

Laminin-1/BM MMP14 nuclear actin Leukocytes TGF-β Mechanical stress

Regulating factors

PTHrP BMP4 BMPR1A FGF10 Mammary bud

Duct

Regulating factors

Bud outgrowth

Cheng-Ming Chuong,1, 3 Ramray Bhat,2 Randall B. Widelitz,1 and Mina J. Bissell2 Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA, 2Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA, 3Center of Wound Repair and Regeneration, Cheng Kung University, Tainan, Taiwan

1

SnapShot: Branching Morphogenesis

Earlier A

1212 Sprouty BMP FGF

Proximal

See online version for legend and references.

SnapShot: Branching Morphogenesis Cheng-Ming Chuong,1, 3 Ramray Bhat,2 Randall B. Widelitz,1 and Mina J. Bissell2 Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA 2 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA 3 Center of Wound Repair and Regeneration, Cheng Kung University, Tainan, Taiwan

1

Ectodermal appendages such as feathers, hair, mammary glands, salivary glands, and sweat glands form branches allowing a much-increased surface for functional differentiation and secretion. There are similarities among these branching organs, not only in their embryonic origin and their architecture, but also in repetitive deployment of some central signaling molecules such as BMPs, TGF-β, FGF, and MMPs, which are used in all branching organs. Details of the molecular and architectural pathways of branching, however, are context dependent. The difference in branching morphogenesis in vivo is based on chemical, mechanical, and geometric cues in the mesenchymal stroma that “sculpt” epithelial progenitors (see, for example, Nelson et al., 2006). Here, we choose the mammary gland and feathers to demonstrate these principles (Widelitz et al., 2007). Once a branched appendage develops, its structure needs to be retained through the life of the individual. In ectodermal branching organs, much of the lush morphogenesis happens after birth. By undergoing cyclic involution and growth, mammary glands and feathers renew their branching phenotypes coupled to body hormone status and seasonal changes for the best possible functional performance (Chuong et al., 2012). Some of the molecules mediating organ specificity remain similar to those involved in organ development, yet they differ in that the former now must prevent the organs from losing their structural and functional identities, ensuring that the mammary gland and the feather, while both branching, remain distinct from each other (Bhat and Bissell, 2014). Mammary Gland: Branching by Invasion Male and female mammals are born with a rudimentary mammary gland referred to as an “anlage.” During puberty, under the action of ovarian hormones, the embryonic anlage undergoes extensive branching by invading into the mammary fat pad in the female and ceases after expanding to the outer limits of the mesenchymal fat pad. The tree-like epithelial network is made of a bilayer of luminal duct or luminal milk-secreting cells, surrounded by myoepithelial cells and basement membrane. Myoepithelial cells provide structural and functional support for their luminal counterparts and, along with the stroma, are responsible for synthesis and organization of the basement membrane. During pregnancy, the alveolar compartment proliferates and expands to prepare for lactation, during which alveolar luminal cells synthesize milk proteins. Milk is ejected by systematic contraction of myoepithelial cells in response to suckling-mediated release of oxytocin. After weaning, the mammary gland involutes. During branching, epithelial cells have to mobilize the necessary machinery for invasion of the growing ducts into the fat pad and the formation of secondary and tertiary branches to complete the eventual adult mammary architecture. This relies on the activities of a number of matrix metalloproteinases (MMPs) (Fata et al., 2004). Although MMPs’ proteolytic activity is central to all branching structures, recent findings show that the signaling function of a number of them is through domains other than their catalytic domains (e.g., Correia et al., 2013; Mori et al., 2013). Whereas the epithelial compartment of human breast is separated from fat tissue by interstitial stroma, mammary epithelial structures in mouse are embedded directly in fat tissue, which distinguishes formation of mammary cancers in mice and humans. Feathers: Branching by Differential Cell Death The basal layer of the cylindrical epithelia of feather filament forms periodic invaginations and segregates into alternating zones of cells destined for proliferation and death. Each valley becomes a marginal plate that will undergo programmed cell death, creating space between barbs. Each ridge becomes a barb ridge with bilaterally positioned barbule plates and centrally positioned axial plates. Axial plate cells will eventually disappear to give space to opening barbules. The initial periodic patterning is triggered by activators and inhibitors that involve BMP signaling, whereas the apoptosis of marginal plates involves Shh signaling and caspase-3. At the follicular level, there is another round of apoptosis including pulp epithelia lying internal to the filament cylinder, feather sheath enclosing the filament cylinder, and barb generative zone located in the posterior follicle. Thus, feather branches open up after the branching pattern is sculpted by programmed cell deaths (Chang et al., 2004). Feathers in different body regions serve different functions and have different branching patterns. The radially symmetric downy feathers mainly in the ventral trunk maintain the endothermy of the animal, whereas the bilaterally symmetric vaned feathers seen in the dorsal trunk and tail are used for communication. The bilateral-asymmetric feathers in the wing allow aerodynamic flight. The developing feathers begin as a cylinder, and their complex shape forms from the distal to proximal end. Feather stem cells form a ring located above the dermal papilla, a mesenchymal signaling center at the follicle base. Epithelial progenitors are displaced upward and, after a distance (marked as m, m1, m2), will undergo branching morphogenesis. The morphology (shaft or different branching patterns) reflects the cues received from the follicular microenvironment when progenitor cells are generated. A Wnt3a gradient is responsible for the tilting of the stem cell ring and parallel barb ridges toward the anterior side, thus converting radially symmetric feathers to bilaterally symmetric ones (Yue et al., 2006). Abbreviations Ant, anterior; BGZ, barb generative zone; BM, basement membrane; BMP, bone morphogenetic protein; BMPR1A, BMP receptor 1A; ECM, extracellular matrix; ER-a, estrogen receptor a; FGF, fibroblast growth factor; FGFR2, FGF receptor 2; GATA-3, GATA-binding protein 3; HGFR, hepatocyte growth factor receptor; HS2ST, heparan sulfate 2-Osulfotransferase; HSP90b, heat-shock protein 90 b; MMP, matrix metalloproteinase; NCAM, neural cell adhesion molecule; NDST1, N-deacetylase/N-sulfotransferase 1; Post, posterior; PR-B, progesterone receptor-B; Ptc1, patched homolog 1; PTHrP, parathyroid hormone-related protein; Shh, Sonic hedgehog; SnoN, Ski-related novel protein N; SOCS1, suppressor of cytokine signaling 1; STAT, signal transducer and activator of transcription; TGF-b, transforming growth factor-b; TIMP1, tissue inhibitor of metalloproteinases 1; VDR, vitamin D receptor; WNT, int/Wingless. References Bhat, R., and Bissell, M.J. (2014). WIREs Dev. Biol. 3, 147–163. Chang, C.H., Yu, M., Wu, P., Jiang, T.X., Yu, H.S., Widelitz, R.B., and Chuong, C.M. (2004). J. Invest. Dermatol. 122, 1348–1355. Chuong, C.M., Randall, V.A., Widelitz, R.B., Wu, P., and Jiang, T.X. (2012). Physiology (Bethesda) 27, 61–72. Correia, A.L., Mori, H., Chen, E.I., Schmitt, F.C., and Bissell, M.J. (2013). Genes Dev. 27, 805–817. Fata, J.E., Werb, Z., and Bissell, M.J. (2004). Breast Cancer Res. 6, 1–11. Hennighausen, L., and Robinson, G. (2005). Nature Reviews Molecular Cell Biology 6, 715-725. Mori, H., Lo, A.T., Inman, J.L., Alcaraz, J., Ghajar, C.M., Mott, J.D., Nelson, C.M., Chen, C.S., Zhang, H., Bascom, J.L., et al. (2013). Development 140, 343–352. Nelson, C.M., Vanduijn, M.M., Inman, J.L., Fletcher, D.A., and Bissell, M.J. (2006). Science 314, 298–300. Widelitz, R.B., Veltmaat, J.M., Mayer, J.A., Foley, J., and Chuong, C.M. (2007). Semin. Cell Dev. Biol. 18, 255–266. Yue, Z., Jiang, T.X., Widelitz, R.B., and Chuong, C.M. (2006). Proc. Natl. Acad. Sci. USA 103, 951–955.

1212.e1 Cell 158, August 28, 2014 ©2014 Elsevier Inc.  DOI http://dx.doi.org/10.1016/j.cell.2014.08.019