EASTBIO: Emergence of functional polarity in a tubular epithelium

Deanery of Biomedical Sciences
Epithelial tubes are the conduit through which life-sustaining gases, nutrients and fluids are transported. But they do more than simply convey material to and fro – they carry out vital roles in modifying the material passing through. These activities underpin many of the homeostatic functions in our body. As such, the correct development and maturation of transporting epithelial tubes is essential to life.

Epithelial tubes often have a functional polarity written along their proximo-distal (P-D) axis, with different segments containing specialised cell-types to carry out distinct physiological activities. This principle is illustrated nicely in the kidney. The proximal nephron filters the blood to generate a primary urine, which is then modified by the distinct P-D segments in the renal tubule and collecting duct that differ in their transport properties and passive permeabilities to water, salt and urea. It is this sequence of activities along the P-D axis that underscores the emergent properties of the system (i.e. the ability to produce and concentrate urine). With a handful of notable exceptions, we know very little about how P-D axes and segment-specific differentiation are regulated during organogenesis.

The aim of this project is to redress this deficiency. Our major objective is to understand the molecular and cellular mechanisms that establish and pattern P-D functional polarity in a structurally simple, but functionally sophisticated epithelial tube: the insect renal tubule. The insect renal or Malpighian tubule (MpT) is an essential excretory organ that regulates fluid balance, osmolarity and pH. It clears the insect blood (haemolymph), excreting metabolic and foreign toxins encountered through the diet. MpTs are simple, single-cell layered epithelial tubes each containing a relatively small number of cells. The tubule has a functional polarity represented by secretory and reabsorptive segments, which are important for generating and modifying the urine, and segments involved in homeostatic functions such as calcium handling.

The objective of the project is to determine how functional polarity is established and maintained in the Drosophila renal tubule. The main research aims include:
(1) To determine the tissue patterning mechanism(s) that establishes the P-D axis.
(2) To characterise an identified subset of transcription factors that mark specific segments in the renal tubule; we hypothesise these: (a) are targets of the mechanism(s) outlined in aim 1, and (b) control the differentiation of physiologically distinct cell-types (aim 3).
(3) To link the developmental patterning mechanisms to segment-specific cell differentiation and physiological function.

It is anticipated that this work will be widely relevant to P-D axis specification in other organs and tissues.

Beaven, R. and Denholm, B (2018) Release and spread of Wingless is required to pattern the proximo-distal axis of Drosophila renal tubules eLife 2018;7:e35373