Wnt5a Regulates Midbrain Dopaminergic Axon Growth and Guidance

During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM) the cues that guide dopaminergic (DA) axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have been identified as axon guidance molecules. Several Wnts are expressed in the VM where they regulate the birth of DA neurons. Here, we describe that a precise temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal projections by VM DA neurons. In mice at E11.5, Wnt5a is expressed in the VM where it was found to promote DA neurite and axonal growth in VM primary cultures. By E14.5, when DA axons are approaching their striatal target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is capable of repelling DA neurites. Antagonism experiments revealed that the effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase, Rac1 (a component of the non-canonical Wnt planar cell polarity pathway). Moreover, the effects were specific as they could be blocked by Wnt5a antibody, sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further verified in Wnt5a−/− mice, where fasciculation of the medial forebrain bundle (MFB) as well as the density of DA neurites in the MFB and striatal terminals were disrupted. Thus, our results identify a novel role of Wnt5a in DA axon growth and guidance

Evaluation of 18-F-fluoro-2-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) as a staging and monitoring tool for dogs with stage-2 splenic hemangiosarcoma – A pilot study

<div><p>Positron Emission Tomography-Computed Tomography (PET-CT) is routinely used for staging and monitoring of human cancer patients and is becoming increasingly available in veterinary medicine. In this study, 18-fluorodeoxyglucose (¹⁸FDG)-PET-CT was used in dogs with naturally occurring splenic hemangiosarcoma (HSA) to assess its utility as a staging and monitoring modality as compared to standard radiography and ultrasonography. Nine dogs with stage-2 HSA underwent ¹⁸FDG-PET-CT following splenectomy and prior to commencement of chemotherapy. Routine staging (thoracic radiography and abdominal ultrasonography) was performed prior to ¹⁸FDG-PET-CT in all dogs. When abnormalities not identified on routine tests were noted on ¹⁸FDG-PET-CT, owners were given the option to repeat a PET-CT following treatment with eBAT. A PET-CT scan was repeated on Day 21 in three dogs. Abnormalities not observed on conventional staging tools, and most consistent with malignant disease based on location, appearance, and outcome, were detected in two dogs and included a right atrial mass and a hepatic nodule, respectively. These lesions were larger and had higher metabolic activity on the second scans. ¹⁸FDG-PET-CT has potential to provide important prognostic information and influence treatment recommendations for dogs with stage-2 HSA. Additional studies will be needed to precisely define the value of this imaging tool for staging and therapy monitoring in dogs with this and other cancers.</p></div

PET-CT scan #1 from dog 2.

<p>The images from left to right are transverse (A, B, and C), sagittal (D), and dorsal plane (E), all acquired 1 hour following ¹⁸FGD injection. A and B represent the CT and PET transverse images, respectively, whereas C is the fused PET-CT transverse image. D represents the whole body ¹⁸FDG PET-CT scan, and E is the dorsal reconstruction whole body image. Fused and dorsal reconstruction images show increased metabolic activity at the right auricular appendage compared to background tissue. The focal area of uptake at the right auricular appendage is highlighted by the arrow.</p

PET-CT scan #2 from dog 6.

<p>The images from left to right are transverse (A, B, and C), sagittal (D), and dorsal plane (E), all acquired 1 hour following ¹⁸FGD injection. A and B represent the CT and PET transverse images, respectively, whereas C is the fused PET-CT transverse image. D represents the whole body ¹⁸FDG PET-CT scan, and E is the dorsal reconstruction whole body image. The focal area of uptake in the liver in proximity of the apex of the gall bladder is larger and exhibits further increase in metabolic activity compared to PET-CT #1.</p

PET-CT scan #2 from dog 2.

<p>The images from left to right are transverse (A, B, and C), sagittal (D), and dorsal plane (E), all acquired 1 hour following ¹⁸FGD injection. A and B represent the CT and PET transverse images, respectively, whereas C is the fused PET-CT transverse image. D represents the whole body ¹⁸FDG PET-CT scan, and E is the dorsal reconstruction whole body image. Fused and dorsal reconstruction images show further increase in metabolic activity at the right auricular appendage compared to background tissue and growth of the right auricular mass compared to images obtained from PET-CT scan #1. The focal area of uptake at the right auricular appendage is highlighted by the arrow.</p