Embryonal Homeobox Genes-Developmental

CEOsPresented ByDARE, Ezekiel & AROGUNDADE,

Tolulope

LECTURER: Dr. Ajao M.S.

OutlineIntroductionWhat is gene expression?What are homeobox genes?DiscoveryHomeodomainHuman homeotic genesBody formationPositional InformationSummaryClinical Correlations

IntroductionCell differentiation is the development of non-

specialised cells into cells with specialised functions.Examples: muscle cells, liver cell, red blood cells

As organisms grow and develop from fertilised eggs; organs and tissues develop to produce a characteristic form. The process is called morphogenesis.

Both processes are controlled by gene expression

What is gene expression?

Gene expression is the activation of a gene that results in a polypeptide or protein.

Transcription factors

What are Homeobox Genes?

Homeobox genes are a large family of similar genes that direct the formation of many body structures during early embryonic development.

The gene is a unit of information that encodes a genetic characteristic.

Discovery

Homeoboxes were discovered independently in 1983 by Ernst Hafen, Michael Levine, and William McGinnis.The existence of homeoboxes was first discovered in Drosophila.

Homeodomain

Homeobox genes contain a particular DNA sequence that provides instructions for making a string of 60 protein building blocks (amino acids) known as the homeodomain.

Homeotic Genes Master genes of development.

Human Homeobox Genes

In humans, the homeobox gene family contains an estimated 235 functional genes and 65 pseudogenes.Homeobox genes are present on every human chromosome, and they often appear in clusters.

Examples include: HOX, PAX, MSX, DLX

Other Groups of Homeobox Genes

Four general phases for body formation

1. Organize body along major axes

2. Organize into smaller regions (organs, legs)

3. Cells organize to produce body parts

4. Cells themselves change morphologies and become differentiated

Modus OperandiPolarity

• Even before fertilization an egg has a gradient of proteins that help to establish its polarity (which end becomes the head or anterior and which is the tail, posterior)

• After fertilization “Maternal Effect” genes reinforce this polarity and also establish the dorsal (back) and ventral (belly) orientation

• Polarity is the formation of the axis by which the embryo differentiates

Positional information during development

• Each cell receives positional information that tells it where to go and what to become.

• Cells may respond by1. Cell division, 2. cell migration, 3. cell

differentiation or

4. cell death (apoptosis)

Summary Three-dimensional patterning and body plan

formation during embryogenesis are largely attributable to action of homeobox genes, due to their capacity to spatiotemporally regulate the basic processes of differentiation, proliferation, and migration (Manley and Levine, 1985; Han et al., 1989).

Homeobox genes can regulate genes responsible for cell adhesion, migration, proliferation, growth arrest, and the expression of cytokines needed for extracellular matrix interactions (Graba et al., 1997; Svingen and Tonissen, 2006; Hueber et al., 2007)

Clinical correlations…

Synpolydactyly

Synpolydactyly is a joint presentation ofsyndactyly (fusion of digits) and polydactyly (production of supernumerary digits).

This is often a result of a mutation in the HOX D13 gene.

(Malik et al., 2008)

AniridiaAniridia is an eye disorder characterized by a complete or partial absence of the colored part of the eye (the iris).Aniridia is caused by mutations in the PAX6 gene. The PAX6 gene provides instructions for making a protein that is involved in the early development of the eyes, brain and spinal cord (central nervous system), and the pancreas.

Other Anomalies Associated

Axenfeld-Rieger syndromebranchiootorenal syndromecolobomacombined pituitary hormone deficiencycongenital central hypoventilation syndromecongenital fibrosis of the extraocular musclescongenital hypothyroidismcraniofacial-deafness-hand syndromeenlarged parietal foraminafacioscapulohumeral muscular dystrophyfrontonasal dysplasiaGillespie syndromehand-foot-genital syndromeLanger mesomelic dysplasiaLéri-Weill dyschondrosteosismicrophthalmiaMowat-Wilson syndromenail-patella syndromeneuroblastoma

References• McGinnis W, Levine M, Hafen E, Kuroiwa A, Gehring W (1984). "A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes". Nature 308 (5958): 428–33.

• Scott M, Weiner A (1984). "Structural relationships among genes that control development: sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila". Proceedings of the National Academy of Sciences of the United States of America 81 (13): 4115–9

• Graba, Y., Aragnol, D., and Pradel, J. (1997). Drosophila Hox complex downstream targets and the function of homeotic genes. Bioessays 19, 379–388

• Han, K., Levine, M. S., and Manley, J. L. (1989). Synergistic activation and repression of transcription by Drosophila homeobox proteins. Cell 56, 573–583.

• Manley, J. L., and Levine, M. S. (1985). The homeo box and mammalian development. Cell 43, 1–2. doi: 10.1016/0092-8674(85)90002-9

• Hueber, S. D., Bezdan, D., Henz, S. R., Blank, M., Wu, H., and Lohmann, I. (2007). Comparative analysis of Hox downstream genes in Drosophila. Development 134, 381–392.

• Svingen, T., and Tonissen, K. F. (2006). Hox transcription factors and their elusive mammalian gene targets. Heredity (Edinb.) 97, 88–96.