|M.Sc Student||Zohar Adi|
|Subject||Homothorax is Required for Normal Development of the|
Drosophila Renal Tubes
|Department||Department of Medicine||Supervisor||Professor Adi Salzberg|
|Full Thesis text|
The Drosophila melanogaster Malpighian tubules (MT) serve, together with the fly nephrocytes, as a functional equivalent of the mammalian kidney. Significant homology exists between these two systems and the MT serve as a useful model system for studying kidney development. The MTs are composed of two pairs of epithelial tubes that bud from the midgut-hindgut boundary during embryogenesis. These buds grow and migrate in a stereotyped manner, the longer ones in the direction of the head of the embryo, the shorter ones toward the posterior end. The mature tubules consist of two major cell types: the principal cells (PC) and the stellate cells (SC). The PCs transport cations and organic solutes, and constitute the major tubule cell type (~80% of the cells). The SCs transport water and chloride ions. The SCs are of mesodermal origin. They arise from the caudal mesoderm and are recruited into the developing tubules at embryonic stage 12-13. Upon their recruitment into the tubules the SC cells undergo a mesenchymal-to-epithelial transition.
In this work we study the role of the TALE-class homeoprotein Homothorax (Hth) in MT development. Homothorax (Hth) is a homeodomain-containing protein of the Meis family which is known to interact with another homeodomain-containing protein, Extradenticle (Exd). Hth regulates the sub-cellular localization of Exd and is capable of translocating it to the nucleus. Inside the nucleus, Hth and Exd are known to form ternary complexes with Hox proteins, thus affecting their binding specificity.
We have characterized the expression pattern of Hth within the developing tubules and found that Hth expression is restricted to the distal portion of each tubule and that the main role of Hth within the tubules is to translocate Exd to the nucleus. We hypothesize that the differential distribution of Hth is required to define distal versus proximal cell identities along the tubule. Here we show that the difference between distal and proximal identities is required for the correct pattern of bending of the tubule and formation of the leading loop in the right position.
In the absence of Hth the tubules fail to rearrange, migrate and complete their convergent extension without a major change in cell number. Rescue experiments suggest that Hth is required both within the developing tubule and in mesodermal tissues for correct patterning and migration. Inside the tubules Hth defines distal identity whereas outside the tubules, in the mesoderm, it affects the migration of the anterior tubules perhaps by regulating the expression of guiding molecules.