Pancreatic islets are innervated by autonomic and sensory nerves that influence their function. Here, using in vivo time-lapse imaging and genetic analyses in zebrafish, we determined the events leading to islet innervation. Comparable neural density in the absence of vasculature indicates that it is dispensable for early pancreatic innervation. Neural crest cells are in close contact with endocrine cells early in development. We find these cells give rise to neurons that extend axons towards the islet as they surprisingly migrate away. Specific ablation of these neurons partly prevents other neurons from migrating away from the islet resulting in diminished innervation. Thus, our studies establish the zebrafish as a model to interrogate mechanisms of organ innervation, and reveal a novel mode of innervation whereby neurons establish connections with their targets before migrating away. This work was supported in part by NIG-Joint (A).

Figure: Schematic of the sequence of cellular events preceding parasympathetic innervation of the pancreatic islet.

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It is well known that most colon cancer patients harbor mutations in the APC tumor suppressor gene that causes ectopic activation of Wnt signaling. Although APC regulates microtubules in addition to Wnt signaling, roles of this APC function in cancer has not been explored.

In this study, we have shown that the APC protein on the cell cortex binds to spindle microtubules that are responsible for chromosome segregation to regulate stability of microtubules. This APC binding results in suppression of their pulling forces, thereby regulating chromosome segregation.

Colon cancer cells with APC mutations frequently have aberrant chromosomes that can be caused by abnormalities in spindle pulling forces. Therefore, the function of APC in the pulling force regulation we have shown might be involved in oncogenesis.

Figure: Mechanism of pulling force suppression by APC
Pulling forces are generated by the dynein motor protein, when microtubules that reach to the cell cortex shrink. Binding of APC to the plus end of microtubules inhibits their shrinkage, thereby suppressing pulling forces.

Right
In wild type cell, spindle are strongly pulled from the posterior pole and moved posteriorly. During this, the posterior centrosome oscillates vertically due to the strong forces by microtubules. In contrast, the anterior centrosome is relatively stable due to the suppression of pulling forces by APC.
Left
APC inhibition results in oscillation of anterior as well as posterior centrosomes.