Función del gen Whsc1 durante el desarrollo embrionario de ratón

Gálvez García, Blanca (2019). Función del gen Whsc1 durante el desarrollo embrionario de ratón. Proyecto Fin de Carrera / Trabajo Fin de Grado, E.T.S. de Ingeniería Agronómica, Alimentaria y de Biosistemas (UPM), Madrid.


Title: Función del gen Whsc1 durante el desarrollo embrionario de ratón
  • Gálvez García, Blanca
  • Rodríguez Enríquez, Isabel
  • Giraldo Carbajo, Patricia
Item Type: Final Project
Degree: Grado en Biotecnología
Date: June 2019
Faculty: E.T.S. de Ingeniería Agronómica, Alimentaria y de Biosistemas (UPM)
Department: Biotecnología - Biología Vegetal
Creative Commons Licenses: Recognition - No derivative works - Non commercial

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Wolf-Hirschhorn syndrome (WHS) is a rare disease caused by hemizygous subtelomeric deletions of the distal region of the short arm of chromosome 4 (region 4p16.3). Of the different genes that are lost with this deletion, it is the Whsc1 gene, which codes for a histone methyltransferase, the main candidate to be responsible for the different symptoms suffered by WHS patients. These include mental and growth retardation, seizure disorder, immunodeficiencies, midline defects, and bone, heart, and craniofacial disorders. The latter are responsible for the characteristic feature of the disease, known as "Greek warrior helmet". From the functional point of view, it is considered that the most relevant domain of WHSC1 is the SET domain, since it is responsible for remodeling chromatin, modulating the expression of a great variety of genes. However, the specific role of WHSC1 in the alterations of development suffered by patients is unknown, since the deletions that cause this syndrome include other genes located in the 4p16.3 region, which also seem to have a relevant contribution to the development of the disease. To determine the function of the Whsc1 gene in the correct formation of tissues and organs during embryonic development, and to help understand the cause of various alterations suffered by patients, a study was conducted using WHSC1-KO mice, genetically modified to eliminate the SET domain. In this study, mouse embryos WHSC1-KO, WHSC1-HET and WT were stained at different stages of embryonic development with hematoxylin and eosin, which allows to distinguish all tissues, offering a general image of the embryo, and with alcian blue, to be able to observe the possible alterations in the cartilaginous skeletal system of the embryo. In situ hybridization was also performed on sections of embryos WHSC1-KO, WHSC1-HET and WT, with a RNA probe corresponding to the AWS-SET domain of Whsc1, to determine in which organs the expression of this gene is greater, and thus be able to correlate the alterations observed with the expression of the gene. The results obtained in this work, although preliminary, indicate that the Whsc1 gene has a very important function during mouse embryonic development, affecting the correct formation of different tissues and organs. Proof of this is the obvious developmental delay that has been observed in WHSC1-KO embryos, which causes them to die within hours of birth. Alterations in the anterior brain have also been observed in WHSC1-KO and WHSC1-HET embryos, specifically in the mesencephalon and in the cerebral cortex, demonstrating that WHSC1 plays an important role during the development of brain tissue in mice, and that, in hemicigosis, these brain defects also occur. In addition, the expression of Whsc1 observed in brain tissue, both in this study and in previous studies is high, which allows us to reaffirm the importance of this gene in the correct development of the brain. On the other hand, the skeletal alterations observed in WHSC1-KO embryos, such as the reduction of the size of the skull, the abnormal separation of the eyes and the thickening of the palate, demonstrate that WHSC1 has an essential function during the development of the skeletal system in embryos of mouse, and that its lost is sufficient to observe the characteristic craniofacial alterations of the SWH patients. Thus, this work allows us to conclude that, regardless of the role of other genes located in the chromosomal region 4p16.3 in the formation of tissues and organs, the lack of function of WHSC1 is sufficient to produce some of the characteristic clinical manifestations of SWH patients.

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Item ID: 57495
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Deposited by: Biblioteca ETSI Agrónomos
Deposited on: 13 Dec 2019 09:04
Last Modified: 13 Dec 2019 09:04
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