Principles of Development as Learned through the Fly

Much of the basic principles of embryogenesis has been learned through the fruit fly, Drosophila melanogaster. Some of these basic principles are illustrated here:

• Importance of transcription factors and signaling molecules in development:

One example of the importance of transcription factors are the proteins bicoid and hunchback which are important in determining the anterior part of the body (head and thorax) from the posterior part (abdomen) of the fruit fly. Bicoid mRNA is expressed as a bicoid protein resulting in a protein gradient with the highest concentration of protein on the left side of the embryo. Hunchback DNA is only activated once the amount of bicoid protein passes a certain threshold. This results in a sharp borderline which in the developing embryo from the part where hunchback is not expressed to the part where hunchback is expressed.

The Hox genes play a very important role in early embryological development. There are 8 Hox genes in the fly and some 39 Hox genes in humans. These genes lie in clusters. In the fly, for example, the genes lie in two clusters, one cluster which controls the differences among thoracic and head segments and the other which controls differences among the abdominal and thoracic segments of the body. All contain a highly conserved homeobox domain. This homeobox domain encodes a small protein that is a transcription factor (binds DNA & regulates gene activity).

The coding sequences of the 8 HOX genes are interspersed amid a larger quantity of regulatory DNA. This regulatory DNA along with HOX interpretes the multiple items of positional information

One important signalling pathway in animal development is the pathway activated by Hedgehog proteins. Two transmembrane proteins, patched and Smoothened mediate responses to all Hedgehog proteins. Hedgehog is an extra cellular signaling molecule that binds to patched freeing Smoothened from patched. The way that this works is that in the absence of Hedgehog, a gene regulatory protein called Cubitus Interruptus (Ci) is cleaved into a smaller protein that accumulates in the nucleus where it acts as a transcriptional repressor, helping to keep some Hedgehog responsive genes silent. When Hedgehog binds to Patched, this processing is stopped and the uncleaved Ci protein is released from its complex where it enters the nucleus and activates the transcription of Hedgehog target genes. Sonic Hedgehog also can play a role in cancer (it facilitates proliferation by stimulating Ci-coativator complex formation which in turn facilitates activation of cyclins D and E promoters. Inactivating mutations in Patched also allow Ci-coactivator formation as with Hedgehog binding to patched)

• importance of Asymmetrical distribution of gene regulatory proteins and importance of noncoding DNA sequences: One example is the Drosophila even-skipped (eve ) gene. At the earliest stage of development where eve is expressed, the embryo is a single giant cell containing multiple nuclei in a common cytoplasm. But this cytoplasm is not uniform. It contains a mixture of gene regulatory proteins that are distributed unevenly along the length of the embryo, thus providing positional information that distinguishes one part from another. The eve gene contains regulatory noncoding DNA sequences that somehow read the concentrations of gene regulatory proteins at each position along the length of the embryo such that eve is expressed in seven stripes positioned precisely along the anterior-posterior axis of the embryo. When a particular regulatory module for say stripe 2 is removed from its normal position upstream of the eve gene, placed in front of a reporter gene (promoter + B-galactosidase gene) and reintroduced into the fly genome, the reporter gene is found to be expressed in precisely the position of stripe 2. How can this be? The regulatory module contains recognition sequences for 2 gene regulatory proteins (Bicoid and Hunchback) that activate eve transcription and 2 (Kruppel and Giant) that repress it. The relative concentrations of these 4 proteins determine whether protein complexes forming at the stripe 2 module turn on transcription of the eve gene. The regulatory unit combines with these 4 proteins to turn on transcription of eve only in those nuclei that are located where the levels of both Bicoid and Hunchback are high and both Kruppel and Giant are absent. This combination of activators and repressors occurs only in one region of the early embryo whereas everywhere else the stripe 2 module is silent.

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