Editing Morphogenesis (section)

==Cellular basis==

[[File:P19 cell sorting out.png|thumb|upright|Cell sorting out with cultured [[P19 cell|P19 embryonal carcinoma cells]]. Live cells were stained with [[DiI]] (red) or DiO (green). The red cells were [[Genetic engineering|genetically altered]] and express higher levels of [[E-cadherin]] than the green cells. The mixed culture forms large multi-cellular aggregates.]]

At a tissue level, ignoring the means of control, morphogenesis arises because of cellular proliferation and motility.<ref>{{Cite journal |last1=Montévil |first1=Maël|last2=Speroni |first2=Lucia |last3=Sonnenschein |first3=Carlos |last4=Soto |first4=Ana M. |date=2016 |title=Modeling mammary organogenesis from biological first principles: Cells and their physical constraints|journal=Progress in Biophysics and Molecular Biology |series=From the Century of the Genome to the Century of the Organism: New Theoretical Approaches |volume=122 |issue=1 |pages=58–69 |doi=10.1016/j.pbiomolbio.2016.08.004 |pmid=27544910|pmc=5563449 |arxiv=1702.03337 }}</ref> Morphogenesis also involves changes in the cellular structure<ref>{{Cite journal|last1=Duran-Nebreda|first1=Salva|last2=Pla|first2=Jordi|last3=Vidiella|first3=Blai|last4=Piñero|first4=Jordi|last5=Conde-Pueyo|first5=Nuria|last6=Solé|first6=Ricard|date=2021-01-15|title=Synthetic Lateral Inhibition in Periodic Pattern Forming Microbial Colonies|journal=ACS Synthetic Biology|volume=10|issue=2|language=en|pages=277–285|doi=10.1021/acssynbio.0c00318|pmc=8486170 |pmid=33449631|issn=2161-5063}}</ref> or how cells interact in tissues. These changes can result in tissue elongation, thinning, folding, invasion or separation of one tissue into distinct layers. The latter case is often referred as [[cell sorting]]. Cell "sorting out" consists of cells moving so as to sort into clusters that maximize contact between cells of the same type. The ability of cells to do this has been proposed to arise from differential cell adhesion by [[Malcolm Steinberg]] through his [[differential adhesion hypothesis]]. Tissue separation can also occur via more dramatic [[cellular differentiation]] events during which epithelial cells become mesenchymal (see [[Epithelial–mesenchymal transition]]). Mesenchymal cells typically leave the epithelial tissue as a consequence of changes in cell adhesive and contractile properties. Following epithelial-mesenchymal transition, cells can migrate away from an epithelium and then associate with other similar cells in a new location.<ref>{{cite book |author=Gilbert, Scott F. |title=Developmental biology |publisher=Sinauer Associates |location=Sunderland, Mass |year=2000 |isbn=978-0-87893-243-6 |edition=6th |chapter=Morphogenesis and Cell Adhesion |chapter-url=https://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=morphogenesis&rid=dbio.section.372 |url-access=registration |url=https://archive.org/details/developmentalbio00gilb }}</ref> In plants, cellular morphogenesis is tightly linked to the chemical composition and the mechanical properties of the cell wall.<ref name=Bidhendi2016>{{cite journal|last1=Bidhendi|first1=Amir J|last2=Geitmann|first2=Anja|title=Relating the mechanical properties of the primary plant cell wall to morphogenesis. |url=https://academic.oup.com/jxb/article-pdf/67/2/449/9366354/erv535.pdf|journal=Journal of Experimental Botany|date=January 2016|volume=67|issue=2|pages=449–461|doi=10.1093/jxb/erv535|pmid=26689854|doi-access=free}}</ref><ref name=Bidhendi2018>{{cite journal|last1=Bidhendi|first1=Amir J|last2=Geitmann|first2=Anja|title=Finite element modeling of shape changes in plant cells|journal=Plant Physiology|date=January 2018|volume=176|issue=1|pages=41–56|doi=10.1104/pp.17.01684|pmid=29229695|pmc=5761827}}</ref>

===Cell-to-cell adhesion===
During embryonic development, cells are restricted to different layers due to differential affinities. One of the ways this can occur is when cells share the same cell-to-[[cell adhesion molecule]]s. For instance, homotypic cell adhesion can maintain boundaries between groups of cells that have different adhesion molecules. Furthermore, cells can sort based upon differences in adhesion between the cells, so even two populations of cells with different levels of the same adhesion molecule can sort out. In [[cell culture]] cells that have the strongest adhesion move to the center of a mixed aggregates of cells. Moreover, cell-cell adhesion is often modulated by cell contractility, which can exert forces on the cell-cell contacts so that two cell populations with equal levels of the same adhesion molecule can sort out. The molecules responsible for adhesion are called cell adhesion molecules (CAMs). Several types of cell adhesion molecules are known and one major class of these molecules are [[cadherin]]s. There are dozens of different cadherins that are expressed on different cell types. Cadherins bind to other cadherins in a like-to-like manner: [[E-cadherin]] (found on many epithelial cells) binds preferentially to other E-cadherin molecules. Mesenchymal cells usually express other cadherin types such as N-cadherin.<ref>{{cite journal |author1=Hulpiau, P. |author2=van Roy, F. |title=Molecular evolution of the cadherin superfamily |journal=Int. J. Biochem. Cell Biol. |volume=41 |issue=2 |pages=349–69 |date=February 2009 |pmid=18848899 |doi=10.1016/j.biocel.2008.09.027}}</ref><ref>{{cite journal |author1=Angst, B. |author2=Marcozzi, C. |author3=Magee, A. |title=The cadherin superfamily: diversity in form and function |journal=J Cell Sci |volume=114 |issue=Pt 4 |pages=629–41 |date=February 2001 |doi=10.1242/jcs.114.4.629 |pmid=11171368}}</ref>

===Extracellular matrix===
The [[extracellular matrix]] (ECM) is involved in keeping tissues separated, providing structural support or providing a structure for cells to migrate on. [[Collagen]], [[laminin]], and [[fibronectin]] are major ECM molecules that are secreted and assembled into sheets, fibers, and gels. Multisubunit transmembrane receptors called [[integrin]]s are used to bind to the ECM. Integrins bind extracellularly to fibronectin, laminin, or other ECM components, and intracellularly to [[microfilament]]-binding proteins [[Actinin alpha 1|α-actinin]] and [[talin (protein)|talin]] to link the [[cytoskeleton]] with the outside. Integrins also serve as receptors to trigger [[signal transduction]] cascades when binding to the ECM. A well-studied example of morphogenesis that involves ECM is [[mammary gland]] ductal branching.<ref>{{cite journal |vauthors=Fata JE, Werb Z, Bissell MJ |title=Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes |journal=Breast Cancer Res. |volume=6 |issue=1 |pages=1–11 |year=2004 |pmid=14680479 |pmc=314442 |doi=10.1186/bcr634 |doi-access=free }}</ref><ref name="Sternlicht"/>

===Cell contractility===
Tissues can change their shape and separate into distinct layers via cell contractility. Just as in muscle cells, [[myosin]] can contract different parts of the cytoplasm to change its shape or structure. Myosin-driven contractility in embryonic tissue morphogenesis is seen during the separation of [[germ layer]]s in the [[model organism]]s ''[[Caenorhabditis elegans]]'', ''[[Drosophila]]'' and [[zebrafish]]. There are often periodic pulses of contraction in embryonic morphogenesis. A model called the cell state splitter involves alternating cell contraction and expansion, initiated by a bistable organelle at the apical end of each cell. The organelle consists of [[microtubule]]s and [[microfilament]]s in mechanical opposition. It responds to local mechanical perturbations caused by morphogenetic movements. These then trigger traveling [[embryonic differentiation waves]] of contraction or expansion over presumptive tissues that determine cell type and is followed by cell differentiation. The cell state splitter was first proposed to explain [[neural plate]] morphogenesis during [[gastrulation]] of the [[axolotl]]<ref>{{Cite journal | doi=10.1007/BF02797122| pmid=2450659|title = The cytoskeletal mechanics of brain morphogenesis| journal=Cell Biophysics| volume=11| pages=177–238|year = 1987|last1 = Gordon|first1 = Richard| last2=Brodland| first2=G. Wayne| s2cid=4349055}}</ref> and the model was later generalized to all of morphogenesis.<ref>{{Cite journal | doi=10.1186/s12976-016-0037-2| pmid=26965444| pmc=4785624|title = The organelle of differentiation in embryos: The cell state splitter| journal=Theoretical Biology and Medical Modelling| volume=13| pages=11|year = 2016|last1 = Gordon|first1 = Natalie K.| last2=Gordon| first2=Richard| doi-access=free}}</ref><ref>{{Cite book | doi=10.1142/8152|title = Embryogenesis Explained|year = 2016|last1 = Gordon|first1 = Natalie K.| last2=Gordon| first2=Richard| isbn=978-981-4350-48-8}}</ref>

===Branching morphogenesis===
{{Further|Lung#Development|Breast development}}
In the development of the [[lung]] a bronchus branches into bronchioles forming the [[respiratory tree]].<ref name="Wolpert">{{cite book|last1=Wolpert|first1=Lewis|title=Principles of development|date=2015|publisher=Oxford University Press|isbn=978-0-19-967814-3|pages=499–500|edition=5th}}</ref> The branching is a result of the tip of each bronchiolar tube bifurcating, and the process of branching morphogenesis forms the bronchi, bronchioles, and ultimately the alveoli.<ref name="Miura">{{Cite book|last1=Miura|first1=T|title=Multiscale Modeling of Developmental Systems|date=2008|volume=81|pages=291–310|doi=10.1016/S0070-2153(07)81010-6|pmid=18023732|series=Current Topics in Developmental Biology|isbn=9780123742537|chapter=Modeling Lung Branching Morphogenesis}}</ref>

Branching morphogenesis is also evident in the [[Mammary duct|ductal formation]] of the [[mammary gland]].<ref>{{cite journal |vauthors=Fata JE, Werb Z, Bissell MJ |title=Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes |journal=Breast Cancer Res. |volume=6 |issue=1 |pages=1–11 |year=2004 |pmid=14680479 |pmc=314442 |doi=10.1186/bcr634 |doi-access=free }}</ref><ref name="Sternlicht">{{cite journal |author=Sternlicht MD |title=Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis |journal=Breast Cancer Res. |volume=8 |issue=1 |pages=201 |year=2006 |pmid=16524451 |pmc=1413974 |doi=10.1186/bcr1368 |doi-access=free }}</ref> Primitive duct formation begins in [[prenatal development|development]], but the branching formation of the duct system begins later in response to [[estrogen]] during puberty and is further refined in line with mammary gland development.<ref name="Sternlicht"/><ref name="HynesWatson2010">{{cite journal|last1=Hynes|first1=N. E.|last2=Watson|first2=C. J.|title=Mammary Gland Growth Factors: Roles in Normal Development and in Cancer|journal=Cold Spring Harbor Perspectives in Biology|volume=2|issue=8|year=2010|pages=a003186|issn=1943-0264|doi=10.1101/cshperspect.a003186|pmid=20554705|pmc=2908768}}</ref><ref name="HarrisLippman2012">{{cite book|author1=Jay R. Harris|author2=Marc E. Lippman|author3=C. Kent Osborne|author4=Monica Morrow|title=Diseases of the Breast|url=https://books.google.com/books?id=GLc8xYe239kC&pg=PT94|date=28 March 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-4870-1|pages=94–}}</ref>