Nerdy Science Blog

When I was sorting files in my computer, I came across a cell biology essay I wrote last year.  I remember that a lot of people didn’t want to choose this topic, but I simply like it.  There are not so many resources as other topics, and this gives me opportunity to write my own craps.

I realized most of the assignments topics I chose to do are not everyone’s favor.  I just like to challenge things (even if I don’t get good grades).  There might be some grammar and spelling errors in the following essay.

Describe the role of cadherin swapping during early embryonic mouse development. 

1. Introduction

Mouse has been used as model organism in many researches as it is cheap, highly reproductive, sharing many similarities with human and even has the same genome size as human.  The earliest stages of mouse embryonic development are known as cleavage, gastrulation, and neurulation.  These stages are also corresponding to the human one (Lodish et al., 2004; Karp, 2005).  In the cleavage stage, cell-cell adhesion appears to be an important process.  Cell-cell adhesion requires cell adhesion molecules (CAMs).  There are four types of CAMs, which are cadherins, immunoglobulin (Ig) superfamily, integrins, and selectins.  Cadherins appear to be the major CAMs.  They are essential for the cells adhesion, however cells adhesion is not the only function they have.  They are also functional for recognition and sorting of cells, tissue morphogenesis,  maintainence of structures and tissues, and coordinate the cells movement throughout the whole mouse development.  There are different type of cadherins such as classical cadherins, protocadherins, and atypical cadherins.  Cadherins are calcium ion dependent, which means they only work when there are the presence of calcium ions.  The constant changing of embryonic development also has changes in cadherins expression during the early stage of embryogenesis.  Classical cadherins are especially important at the early stage of embryogenesis, which later lead to developing healthy adult mouse (Alberts et al., 2002; Halbeib and Nelson, 2006; Lodish et al., 2004).

2. Early Life Cycle of Mouse

Life cycle of mouse is 9 weeks which makes it a model organism in mammalian researches.  Embryogenesis of mouse starts when an egg is fertilized.  Three days after the egg is fertilized, which is protected by external coat, the zona pellucida, it divides and generates into 16 cells which are known as blastomeres.  These blastomeres are loosely packed.  Then compaction occurs between the blastomeres forming morula, which is a solid ball of cells.  Morula is then converted into blastocyst through cell-cell adhesion.  The cells are polarized after compaction which the nonpolarized cells become inner cell mass, whereas others become trophectoderm.  Inner cell mass will give rice to embryo proper and trophectoderm will form extra-embryonic structures.  On the fourth day, embryo makes contact with the uterus wall and starts to form placenta (Alberts et al., 2002; Wolpert et al., 2002).  Gastrulation is the first specification of mammalian embryo.  Ectoderm, endoderm and mesoderm are the three main tissues form in gastrulation and each of them will develop into different body parts.  The mouse embryo undergoes neurulation after gastrulation, which neural tube is formed which can later develop into brain and spinal cord.  Neurulation and gastrulation occurs from day 7 to 10.5, then follows by organogenesis stage (Vleminckx and Kemler, 1999; Wolpert et al., 2002).

3. Cleavage Stage

Classical cadherins, which can be found at adherens junction, are subdivided into type I and type II.  Epithelial (E) cadherin is type I classical cadherin, which is commonly found in mature epithelial cells adherens junctions.  E-cadherin is also the earliest cadherin being expressed during the development of mouse embryo (Alberts et al., 2002; Halbeib and Nelson, 2006).  Cell-cell adhesion requires CAMs.  There are several types of cell-cell adhesion binding, which are homophilic binding, heterophilic binding, and linker-dependent binding.  Most of the cadherins are using homophilic binding, which means the cells are bind together by the same molecules.  E-cadherin is important in both cell adhesion and cell shaping.  In the presence of extracellular calcium ions, it triggers the compaction of blastomeres, which are loosely packed.  E-cadherins spread evenly on the surfaces of blastomeres.  The distribution of E-cadherins on blastomeres surface are controlled by protein phosphorylation or dephosphorylation.  Blastomeres are firmly attached together by intercellular junctions through E-cadherins homophilic binding.  Transduction of kinase C may activate E-cadherins.  Ankyrin-G and β-2-spectrin are required in the activity of E-cadherin of cell-cell contact and stabilizing membrane.  By inactivating E-cadherin in mouse using antibodies against E-cadherin, the embryo fails to undergo compaction as the antibodies block the blastomeres.  Deficiency of E-cadherin in embryo will cause the embryo die at blastocyst stage (Alberts et al., 2002; Wolpert et al., 2002; Vries et al., 2004; Kizhatil et al., 2007; Kawai et al., 2002). 

In the mouse embryonic stem (ES) cell where the E-cadherin gene allele was knocked out, the cell showed a disaggregated phenotype in culture and this indicated that E-cadherin is important in polarization of ectoderm (Vleminckx and Kemler, 1999).  However without maternal E-cadherin, blastomeres can be bind together by zona pellucida.  Zygotically produced E-cadherin at morula stage can then restore the adhesion process.  Kan and other researchers (2007) had replaced E-cadherin gene allele with neuronal (N) cadherin to observe the normality of embryogenesis.  The replacement showed that cells compaction was carried out as usual but N-cadherin could not replace E-cadherin during the formation of trophectoderm.  This indicates that E-cadherin increases the success rates of embryonic development.  E-cadherin is also important to blastocyst and formation of trophectoderm, which is the first epithelial structure (Lien et al, 2006). 

E-cadherin might take an important role in embryo implantation onto uterus wall.  By treating E-cadherin antibodies, the embryo implantation was inhibited (Liu et al., 2006).  Jha and other researchers (2006) observed that there are E-cadherin found on both blastocyst and uterus wall, and there is less regulation on E-cadherin and calcium ions which increase the adhesiveness of embryo and uterus wall.  These findings suggest that deficiency in E-cadherin could cause miscarriage.   Another type I cadherin, P-cadherin is also important in the attachment of placenta stick to the uterus (Gilbert and Singer, 2006).

4. Gastrulation

Mass migration occurs during gastrulation.  The migration needs cadherins for regulation. The adsence of cadherins in the development of the mouse might show abnormalities in growth.  E-cadherin is inactivated for the first time at the gastrulation stage in mesoderm and expressed N-cadherin.  E-cadherin is downregulated by p38 and p38-interacting protein at this stage, whereas expression of N-cadherin is initiated by transcription twist (Larue et al., 1996; Derycke and Bracke, 2004; Zohn et al., 2006).  Mesoderm will later developed into internal organs, like kidneys (Wolpert et al., 2002).  Although E-cadherin is downregulated in the mesoderm, it is still being expressed in all epithelia. 

N-cadherin is one of the type I classical cadherin.  N-cadherin is important in tissue formation, including cardiac development.  During the cardiac development, N-cadherin sorts out precardiac mesoderm, establishes left-right asymmetry, morphogenesis of cardiac looping as well as trabeculation of myocardial wall.  N-cadherin is expressed by ventral mesoderm cells of primordia.  This is to sort the cells out from dorsal mesoderm cells and join to form an epithelium by connecting together.  Pericardial cavity is then formed and the cells will downregulate N-cadherin.  The downregulation of N-cadherin changes epithelium to endocardium, which is the lining of heart.  Epithelial cells is then forming myocardium which will develop into heart muscle.  Deficiency of N-cadherin in mouse embryogenesis, embryo of mouse died at day 9 to 10 because of the defective heart (Gilbert and Singer, 2006; Alberts et al., 2002; Halbleib and Nelson, 2006; Vleminckx and Kemler, 1999; Stemmler et al., 2003; Derycke and Bracke, 2004).

5. Neurulation

Formation of neural tube happens in neurulation stage.  There are overlapping of several cadherins at this stage which later lead to brain formation.  Neural tube originally is part of ectoderm.  During the neurulation, there are changes in cells adhesion.  Cells of neural plate express L-CAM initially and neural folds develop.  E-cadherin starts to switch to N-cadherin at neural plate.  N-cadherin and N-CAM are express by the neural plate ectoderm, whereas E-cadherin is express at the adjacent ectoderm.  E-cadherin is expressed until neural tube is formed.  Then N-cadherin and N-CAM are produced after E-cadherin is stop from producing.  This causes neural tube tissues no longer adhering with ectoderm surface.  Injection of N-cadherin into the adjacent ectoderm will slow down the separation of neural tube from epidermis.  Because of N-cadherin expressed during neurulation, neural crest cells are created after formation of neural tube.  N-cadherin is downregulated and neural crest cells are free to move around, which later develop into different body parts.  The initiation of neurulation is not affected without N-cadherin, however knockout of N-cadherin not only will cause mouse die of defective heart on day 10, but also because of malformed neural tubes (Redies et al., 2003; Gilbert and Singer, 2006; Wolpert et al., 2002; Derycke and Bracke, 2004; Halbleib and Nelson, 2006).

6. Somitogenesis

After neural tube is formed, there is a stage call somitogenesis which form somites that will eventually turn into muscle, spinal vertebrae, and dermis.  Somites are formed in presomatic mesoderm.  Somites are formed every 120 minutes in mouse.  Deficiency in N-cadherin will produce small, irregularly shaped, less cohesive, and partially distupted somites.  This will affect the morphogenesis process.  Somite segmentation is also induced by protocadherin 10  (Gilbert and Singer, 2006; Radish et al., 1997; Wolpert et al., 2002; Murakami et al., 2006)

7. Conclusion

There are many different kinds of cadherins, namely classical cadherins, protocadherins, and atypical cadherins.  Swapping of cadherins are important in early stage of mouse embryonic development.  There are two major cadherins in this early stage, which are E-cadherin and N-cadherin.  Both of them belong to the classical cadherins.  They are crucial in early embryogenesis stages, such as cleavage, gastrulation, and neurulation.  They are also important for further development of mouse.  The studies of early stage of mouse embryogenesis provide an overview of cadherin swapping in other mammalian, such as human, which can help to tackle down potential diseases and have better understanding of the development of mammals.  Further studies can be made to discover if there are other cadherins that are involved in early stages of embryogenesis and also to determine if there are other proteins that can replace cadherins to aid in normal embryogenesis.

References:

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Kan, N.G., Stemmler, M.P., Junghans, D., Kanzler, B., Vries, W.N.D., Dominis, M. and Kemler, R. (2007), Gene Replacement Reveals a Specific Role for E-Cadherin in the Formation of a Functional Trophectoderm, Development, vol 134, pp. 31-41.
 
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Redies, C., Treubert-Zimmermann, U. and Luo, J. (2003), Cadherins as Regulators for the Emergence of Neural Nets from Embryonic Divisions, Journal of Physiology, pp. 5-15. 

Stemmler, M.P., Hecht, A., Kinzel, B. and Kemler, R. (2003), Analysis of Regulatory Elements of E-Cadherin With Reporter Gene Constructs in Transgenic Mouse Embryos, Development Mental Dynamics, vol. 227, pp. 238-245. 

Vleminckx, K. and Kemler, R. (1999), Cadherins and Tissue Formation: Integrating Adhesion and Signaling, BioEssays, vol. 21, pp. 211 – 220. 

Vries, W.N.D., Evsikov, A.V., Haac, B.E., Fancher, K.S., Holbrook, A.E., Kemler, R., Solter, D. and Knowles, B.B. (2004), Maternal b-catenin and E-cadherin in mouse development, Development, vol. 131, no. 18, pp. 4434-4445. 

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