Hertwig's rule, or the long axis rule states that a cell divides along its long axis. Introduced by the German zoologist

Oscar Hertwig Oscar Hertwig (21 April 1849 in Friedberg – 25 October 1922 in Berlin) was a German embryologist and zoologist known for his research in developmental biology and evolution. Hertwig is credited as the first person to observe sexual reproduc ...

in 1884, the rule emphasizes the cell shape as a default mechanism of

spindle apparatus In cell biology, the spindle apparatus is the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter Cell (biology), cells. It is referred to as the mitotic spindle during mitos ...

orientation. Hertwig's rule predicts cell division orientation, which is important for tissue architecture, cell fate and

morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...

Discovery

Hertwig's experiments studied the orientation of frog egg divisions. The frog egg has a round shape and the first division occurs in a random orientation. Hertwig compressed the egg between two parallel plates. The compression forced the egg to change its shape from round to elongated. Hertwig noticed that elongated egg divides not randomly, but orthogonally to its long axis. The new daughter cells were formed along the longest axis of the cell. This observation thus became known as 'Hertwig's rule' or 'long axis rule'.

Confirmation and mechanism

TCJ orients spindle apparatus during cell division

Recent studies in animal and plant systems support the 'long axis rule'. The studied systems include the mouse embryo, ''

Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...

epithelium Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

, ''

Xenopus ''Xenopus'' () (Gk., ξενος, ''xenos'' = strange, πους, ''pous'' = foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described with ...

blastomeres In biology, a blastomere is a type of cell produced by cell division (cleavage) of the zygote after fertilization; blastomeres are an essential part of blastula formation, and blastocyst formation in mammals. Human blastomere characteristics In ...

(Strauss 2006),

MDCK Madin-Darby canine kidney (MDCK) cells are a model mammalian cell line used in biomedical research. MDCK cells are used for a wide variety of cell biology studies including cell polarity, cell-cell adhesions (termed adherens junctions), collectiv ...

cell monolayers and plants (Gibson et al., 2011). The mechanism of the 'long axis rule' relies on

interphase Interphase is the active portion of the cell cycle that includes the G1, S, and G2 phases, where the cell grows, replicates its DNA, and prepares for mitosis, respectively. Interphase was formerly called the "resting phase," but the cell i ...

cell long axis sensing. However, during division many animal cell types undergo cell rounding, causing the long axis to disappear as the cell becomes round. It is at this rounding stage that the decision on the orientation of the cell division is made by the

. The spindle apparatus rotates in the round cell and after several minutes the spindle position is stabilised preferentially along the interphase cell long axis. The cell then divides along the spindle apparatus orientation. The first insights into how cells could remember their long axis came from studies on the ''Drosophila'' epithelium. The study indicated the participation of tricellular junctions (TCJs) in determining the spindle orientation. TCJs localized at the regions where three or more cells meet. As cells round up during mitosis, TCJs serve as spatial landmarks. The orientation of TCJs remains stable, independent of the shape changes associated with cell rounding. The positions of TCJs encode information about interphase cell shape

anisotropy Anisotropy () is the structural property of non-uniformity in different directions, as opposed to isotropy. An anisotropic object or pattern has properties that differ according to direction of measurement. For example, many materials exhibit ve ...

to orient division in the rounded mitotic cell. However this study is limited to only one type of epithelia in ''Drosophila melanogaster'' and has not been shown to be true in other epithelial types.

Mechanobiology

It has been shown that mechanical force can cause cells to divide against their long axis and instead with the direction of mechanical stretch in MDCK monolayers.

Importance

Cell divisions along 'long axis' are proposed to be implicated in the morphogenesis, tissue response to stresses and tissue architecture. Division along the long cell axis reduces global tissue stress more rapidly than random divisions or divisions along the axis of mechanical stress. Long-axis division contributes to the formation of isotropic cell shapes within the monolayer.

References

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