Fly sensory organ precursor cells may shed new light on human immunological disorder

London, June 22 (ANI): Researchers at Baylor College of Medicine say that they have made a new finding regarding the Notch signalling pathway in sensory organ precursor cells in the fruit fly that may help unravel the mystery behind an immunological disorder called WisKott-Aldrich syndrome.

Notch signalling helps determine the fate of a number of different cell types in a variety of organisms, including humans.

"This finding provides a model for how Wiskott Aldrich syndrome - a form of selective immunodeficiency in children - occurs," Nature magazine quoted Dr. Hugo Bellen, professor of molecular and human genetics and director of the Program in Developmental Biology at BCM, as saying.

The researchers point out that two daughter cells arise from a single sensory organ precursor mother cell in the fly peripheral nervous system, and that among the daughter cells, Notch is activated in one and not in the other.

The differential activation of signalling leads to two different kinds of cells which arise from the same mother cell, a reason why the researchers used the fruit flies sensory organ precursor cell division as a model to understand how Notch signalling is activated during asymmetric cell division.

Two graduate students in Bellen's laboratory-Akhila Rajan and An-chi Tien-screened fruit fly mutants that have disrupted peripheral nervous system development and identified a mutant with a cluster of neurons.

According to the researchers, this occurs when there is a problem in Notch signalling.

The researchers say that their study has shown that mutations in the Actin-related protein 3 (Arp3), a component of the seven protein Arp2/3 complex, resulted in the loss of Notch signalling.

They say that this occurs because the ligand Delta, a protein that activates the Notch pathway, cannot travel properly within the sensory organ cells in the absence of Arp3 protein.

The research team have also found that, under normal conditions, vesicles or tiny bubbles containing the Notch activating protein Delta travel to the top of the daughter cell to a structure rich in actin.

They reveal that the specialized actin structure contains many membrane protrusions that increase the surface area of cells called microvilli.

Delta containing vesicles traffic to the microvilli under normal circumstances.

In the Arp3 mutants, there are significantly fewer microvilli, but the transport of Delta is compromised in Arp3 mutants, affecting the ability of Delta to activate Notch.

Calling it an important part of the research team's work, Bellen said that Delta is normally presented at the top of the actin structure. It is then encapsulated in the vesicles and travels to the basal, or bottom, of the structure. Delta then travels back to the top of the daughter cells.

Bellen's research team have discovered that the Arp2/3 complex and its activator WASp (Wiskott-Aldrich syndrome protein) function in these daughter cells to transport Delta vesicles to the apical region of the daughter cells.

The researchers say that the ability of Delta to activate Notch is compromised when this complicated trafficking of Delta does not occur.

"It is likely that whatever we have discovered here has a relationship to what is happening in the patients with Wiskott-Aldrich syndrome. The patients with Wiskott-Aldrich syndrome have mutations in a gene called WASp. WASp is an activator of the Arp2/3 complex. In our work we found that WASp is also required for the trafficking of Delta to the top of the actin structure," said Bellen.

Given that the gene WASp is mutated in the patients with Wiskott-Aldrich syndrome, Bellen and his colleagues' work suggests that defects in the presentation of Delta could explain the loss and dysfunction of T-cells in patients with Wiskott-Aldrich syndrome. (ANI)