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HOMEOBOX GENEBY

ADESEJI WASIU ADEBAYO

08/46KA006

Department of Anatomy,

University of Ilorin

ANA 811:MOLECULAR EMBRYOLOGY AND GENETIC ENGINEERING

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OUTLINE

• INTRODUCTION

• DISCOVERY

• HOMEODOMAIN

• HOX GENES

• CONCLUSION

• REFERENCES

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What are Homeobox Genes?

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

• Homeobox is a DNA sequence, around 180 base pairs long, involved in the regulation of patterns of anatomical development (morphogenesis) in animals, fungi and plants.

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

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Discovery

•Homeoboxes were discovered independently in 1983 by Ernst Hafen, Michael Levine, and William McGinnis in Basel (McGinnis et al., 1984) and Matthew P. Scott and Amy Weiner in Bloomington (Scott and Weiner, 1984).

•The existence of homeoboxes was first discovered in fruit fly (Drosophila melanogaster).

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Homeodomain

•Homeobox genes contain a 180 base pairs DNA sequence that provides instructions for making a string of 60 amino acids protein building blocks known as the homeodomain.

•Homeodomain act as transcription factors,

o Bind to DNA and controls transcription of other genes in the cell

o Initiate patterns of gene expression

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Homeotic Genes Master genes of development.

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HUMAN HOX GENE

Human hox genes are collected into homeotic clusters. o       There are 4 homeotic clusters, labelled A,B,C and D,

o Each cluster is situated on a different chromosome.

o   Each homeotic cluster consists of 13 homeotic genes numbered sequentially from 1 to 13. 

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HUMAN HOX GENE

The four numerically corresponding genes for the four different clusters form a paralogous group.  

o The hox genes are responsible for patterning along the antero-posterior axis. o The genes are expressed sequentially beginning with the paralogous group 1, which is expressed firsto The sequential genes specify different segments in cranio-caudal sequence extending from paralogous group 1, which specifies the most cranial structures, to paralogous group 13, which specifies the most caudal structures.

o Thus the first genes to be expressed specify the most cranial structures while the last to be expressed specify the most caudal structures.  This is responsible for the cranio-caudal sequence of development, where the more cranial segments develop slightly before the more caudal structures.  Consequently the upper limb develops ahead of the lower limb.

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DISTAL-LESS GENE (Dlx)

• Dlx genes are involved in the development of the nervous system and of limbs.

• Dlx 1 and Dlx 2 are expressed by migrating cortical interneurons during neurogenesis.

• Other members of the distal-less homeobox group are DLX1, DLX2, DLX3, DLX4, DLX5, and DLX6.

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Other Groups of Homoebox Genes

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Classes of Human Homeoboxes

 1. ANTP class homeoboxes 6.    SINE class homeoboxes

HOXL subclass homeoboxes 7.    TALE class homeboxes and pseudogenes

NKL subclass homeoboxes and pseudogenes

8.    CUT class homeoboxes and pseudogenes

2.  PRD class homeoboxes and pseudogenes

9.    PROS class homeoboxes

3.  LIM class homeoboxes 10.  ZF class homeoboxes and pseudogenes

4.  POU class homeoboxes and pseudogenes

11.  CERS class homeoboxes

5.  HNF class homeoboxes

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FUNCTIONS OF HOMEOBOX

• 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)

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Clinical correlations…

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AniridiaSynpolydactylyAxenfeld-Rieger

syndromeBranchiootorenal

syndromeColobomaCombined pituitary

hormone deficiencyCongenital central

hypoventilation syndromeCongenital fibrosis

of the extraocular muscles

Congenital hypothyroidism

Craniofacial-deafness-hand syndrome

Enlarged parietal foraminafacioscapulohumeral muscular dystrophy

Frontonasal dysplasia

Gillespie syndromehand-foot-genital syndrome

Langer mesomelic dysplasia

Léri-Weill dyschondrosteosis

MicrophthalmiaMowat-Wilson

syndrome

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Synpolydactyly

Mutation in the HOX D13 gene.

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Aniridia

Aniridia with PAX6 gene mutation.

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Axenfeld-rieger syndrome

mutations in one of the genes known as PAX6, PITX2 and FOXC1.

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HOMEOBOX GENE AND GENETIC ENGINEERING

Can we create new organs from our own tissues?

In a study to review potential future methods of curing metabolic disorders such as diabetes, and analyze the capacity to genetically manipulate the developmental fate of a tissue in vivo using "master regulator" genes.• the homeobox gene Pancreatic and Duodenal Homeobox gene-1 were

systemically delivered to liver of mice, by recombinant adenovirus technology, and analyzed whether it induces a developmental shift toward a beta cell phenotype

• PDX-1 is sufficient to activate the endogenous, otherwise silent, mouse insulin 1 and 2 and pro-insulin convertase gene expression in liver.

• PDX-1 expression in liver resulted in a 25-fold increase in hepatic immunoreactive insulin content and a threefold increase in plasma immunoreactive insulin levels, as compared to control adenovirus-treated mice.

(Ferber, 2000).

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CONCLUSION

• Homebox genes are very important factor in normal morphogenesis in animals including human.

• Mutations of these groups of gene lead to abnormal formation of structures.

• Homebox genes might be the gateway in the field of genetic engineering to create new organs from our own tissues

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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.

• Ferber S. (2000). Can we create new organs from our own tissues? Isr Med Assoc J. 2 Suppl:32-6.

• 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.

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