The ALX3 gene, also known as aristaless-like homeobox 3, is a protein coding gene that provides instructions to build a protein which is a member of the homeobox protein family.[5][6][7] This grouping regulates patterns of anatomical development. The gene encodes a nuclear protein that functions as a transcription regulator involved in cell-type differentiation and development.
The ALX3 protein, encoded by the gene, is a transcription factor, meaning that it binds to DNA and obtains control over the action of other genes. The ALX3 protein specifically controls genes that regulate cell growth, proliferation, and migration. This protein is essential for the development of the head and face, specifically the nose. This event begins around the fourth week of development.
At least 7 mutations in the ALX3 gene are known to cause frontonasal dysplasia. The mutations eliminate the function of the ALX3 protein, resulting in decreased ability to bind to DNA. The loss of regulatory function results in uncontrolled cell proliferation and migration during fetal development. One particular form of the disorder, called frontonasal dysplasia type 1, presents with abnormal development of structures in the middle of the face. The most common malformation of this defect is a cleft in the nose, lip, and palate.[8]
ALX3 was first discovered by a group of scientists, led by Hopi Hoekstra, a biologist from Harvard University, that investigated how stripe patterns form in animals. They investigated the Rhabdomys pumiliom, commonly known as the African striped mouse because of the alternating colored stripes observed on its back. One of the members of the team, Ricardo Mallarino, discovered that the stripes were formed during embryogenesis in the mice. Melanocytes, the specialized cells that produce the pigments in the skin, were not active in areas where the lighter stripes were observed. They then researched the genes active in those areas using RNA sequencing. They discovered that ALX3 was expressed in the light hair areas but not in the dark hair areas. They found that all mice expressed the gene on their abdomen but only the African striped mouse expressed it on its back, hence why the strips appear. Protein-DNA binding was then performed to determine where the ALX3 protein binds on the DNA. ALX3 binds to the promoter and represses MITF, which allows transcription to take place when making melanocytes. More tests were performed to confirm the function of ALX3 within the African striped mice. The gene was observed in other rodents such as the North American chipmunks and deemed responsible for the similar outcomes. The differences in evolution amongst the species did not hinder the similarities in the expression of the gene. This led the team to believe that ALX3 may have the same effect in mammals. However, further studies must be completed to confirm that ALX3 is responsible for the same in other mammals.
References
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000156150 - Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000014603 - Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ Pennisi, Elizabeth. "Key to zebra stripes may be found in African mouse". Science. American Association for the Advancement of Science. Retrieved November 2, 2016.
- ↑ Keely, Jim. "How the African Striped Mouse Got Its Stripes". Howard Hughes Medical Institute. Howard Hughes Medical Institute. Retrieved November 2, 2016.
- ↑ "ALX3 ALX homeobox 3". Retrieved 14 April 2015.
- ↑ "ALX3". The Human Protein Atlas. Retrieved 10 May 2015.
- McGonnell IM, Graham A, Richardson J, Fish JL, Depew MJ, Dee CT, Holland PW, Takahashi T (2011). "Evolution of the Alx homeobox gene family: parallel retention and independent loss of the vertebrate Alx3 gene". Evolution & Development. 13 (4): 343–51. doi:10.1111/j.1525-142X.2011.00489.x. PMC 3166657. PMID 21740507.
- Twigg SR, Versnel SL, Nürnberg G, Lees MM, Bhat M, Hammond P, Hennekam RC, Hoogeboom AJ, Hurst JA, Johnson D, Robinson AA, Scambler PJ, Gerrelli D, Nürnberg P, Mathijssen IM, Wilkie AO (2009). "Frontorhiny, a distinctive presentation of frontonasal dysplasia caused by recessive mutations in the ALX3 homeobox gene". American Journal of Human Genetics. 84 (5): 698–705. doi:10.1016/j.ajhg.2009.04.009. PMC 2681074. PMID 19409524.