Although the left and right hemispheres of our brains develop with a high degree of symmetry at both the anatomical and functional levels, it has become clear that subtle structural differences exist between the two sides and that each is dominant in processing specific cognitive tasks. As the result of evolutionary conservation or convergence, lateralization of the brain is found in both vertebrates and invertebrates, suggesting that it provides significant fitness for animal life. This widespread feature of hemispheric specialization has allowed the emergence of model systems to study its development and, in some cases, to link anatomical asymmetries to brain function and behavior. Here, we present some of what is known about brain asymmetry in humans and model organisms as well as what is known about the impact of environmental and genetic factors on brain asymmetry development. We specifically highlight the progress made in understanding the development of epithalamic asymmetries in zebrafish and how this model provides an exciting opportunity to address brain asymmetry at different levels of complexity.

Asymmetry of the Brain: Development and Implications

TGF-β family ligands function in inducing and patterning many tissues of the early vertebrate embryonic body plan. Nodal signaling is essential for the specification of mesendodermal tissues and the concurrent cellular movements of gastrulation. Bone morphogenetic protein (BMP) signaling patterns tissues along the dorsal-ventral axis and simultaneously directs the cell movements of convergence and extension. After gastrulation, a second wave of Nodal signaling breaks the symmetry between the left and right sides of the embryo. During these processes, elaborate regulatory feedback between TGF-β ligands and their antagonists direct the proper specification and patterning of embryonic tissues. In this review, we summarize the current knowledge of the function and regulation of TGF-β family signaling in these processes. Although we cover principles that are involved in the development of all vertebrate embryos, we focus specifically on three popular model organisms: the mouse Mus musculus, the African clawed frog of the genus Xenopus, and the zebrafish Danio rerio, highlighting the similarities and differences between these species.

/pdf/tgf-b-family-signaling-in-early-vertebrate-development-486iv5rprd.pdf

TGF-β Family Signaling in Early Vertebrate Development

Calcific aortic valve disease: mechanisms, prevention and treatment

Calcific aortic valve disease is dramatically increasing in global burden, yet no therapy exists outside of prosthetic replacement. The increasing proportion of younger and more active patients mandates alternative therapies. Studies suggest a window of opportunity for biologically based diagnostics and therapeutics to alleviate or delay calcific aortic valve disease progression. Advancement, however, has been hampered by limited understanding of the complex mechanisms driving calcific aortic valve disease initiation and progression towards clinically relevant interventions.

Inflammatory and Biomechanical Drivers of Endothelial-Interstitial Interactions in Calcific Aortic Valve Disease.

https://www.cell.com/current-biology/pdf/S0960-9822(14)00984-1.pdf

Tcf7l2 Is Required for Left-Right Asymmetric Differentiation of Habenular Neurons

Left-right (L/R) asymmetries in the brain are thought to underlie lateralised cognitive functions. Understanding how neuroanatomical asymmetries are established has been achieved through the study of the zebrafish epithalamus. Morphological symmetry in the epithalamus is broken by leftward migration of the parapineal, which is required for the subsequent elaboration of left habenular identity; the habenular nuclei flank the midline and show L/R asymmetries in marker expression and connectivity. The Nodal target pitx2c is expressed in the left epithalamus, but nothing is known about its role during the establishment of asymmetry in the brain. We show that abrogating Pitx2c function leads to the right habenula adopting aspects of left character, and to an increase in parapineal cell numbers. Parapineal ablation in Pitx2c loss of function results in right habenular isomerism, indicating that the parapineal is required for the left character detected in the right habenula in this context. Partial parapineal ablation in the absence of Pitx2c, however, reduces the number of parapineal cells to wild-type levels and restores habenular asymmetry. We provide evidence suggesting that antagonism between Nodal and Pitx2c activities sets an upper limit on parapineal cell numbers. We conclude that restricting parapineal cell number is crucial for the correct elaboration of epithalamic asymmetry.

Pitx2c ensures habenular asymmetry by restricting parapineal cell number

Objective
Macrophages have been described in calcific aortic valve disease, but it is unclear if they
promote or counteract calcification. We aimed to determine how macrophages are involved in
calcification using the Notch1+/- model of calcific aortic valve disease.
Approach and Results
Macrophages in wild-type and Notch1+/- murine aortic valves were characterized by flow
cytometry. Macrophages in Notch1+/- aortic valves had increased expression of MHCII. We then
used bone marrow transplants to test if differences in Notch1+/- macrophages drive disease.
Notch1+/- mice had increased valve thickness, macrophage infiltration, and M1-like macrophage
polarization regardless of transplanted bone marrow genotype. In vitro approaches confirm that
Notch1+/- aortic valve cells promote macrophage invasion as quantified by migration index and
M1-like polarization quantified by Ly6C and CCR2 positivity regardless of macrophage
genotype. Finally, we found that macrophage interaction with aortic valve cells promotes
osteogenic, but not dystrophic, calcification by decreasing abundance of the STAT3β isoform.
Conclusions
This study reveals that Notch1+/- aortic valve disease involves increased macrophage
recruitment and polarization driven by altered aortic valve cell secretion, and that increased
macrophage recruitment promotes osteogenic calcification through STAT3 splicing changes.
Further investigation of STAT3 and macrophage-driven inflammation as therapeutic targets in
calcific aortic valve disease is warranted.

/pdf/macrophages-promote-aortic-valve-cell-calcification-through-4io8rg7d0h.pdf

Macrophages Promote Aortic Valve Cell Calcification Through STAT3 Splicing

Objective: Macrophages have been described in calcific aortic valve disease, but it is unclear if they promote or counteract calcification. We aimed to determine how macrophages are involved in cal...

Macrophages Promote Aortic Valve Cell Calcification and Alter STAT3 Splicing.

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Pitx2c ensures habenular asymmetry by restricting parapineal cell number

Macrophages Promote Aortic Valve Cell Calcification Through STAT3 Splicing

Macrophages Promote Aortic Valve Cell Calcification and Alter STAT3 Splicing.