Faculty Bibliography

A major problem in the field of neurodegeneration is the basis of selective vulnerability of subsets of neurons to disease. In aging, Alzheimer's disease (AD), and other disorders such as temporal lobe epilepsy, the superficial layers of the entorhinal cortex (EC) are an area of selective vulnerability. In AD, it has been suggested that the degeneration of these neurons may play a role in causing the disease because it occurs at an early stage. Therefore, it is important to define the distinctive characteristics of the EC that make this region particularly vulnerable. It has been shown that neurotrophins such as brain-derived neurotrophic factor (BDNF) are critical to the maintenance of the cortical neurons in the adult brain, and specifically the EC. Here we review the circuitry, distinctive functions, and neurotrophin-dependence of the EC that are relevant to its vulnerability. We also suggest that a protein that is critical to the actions of BDNF, the ARMS/Kidins220 scaffold protein, plays an important role in neurotrophic support of the EC.

Gli3 is a transcriptional regulator of Hedgehog (Hh) signaling that functions as a repressor (Gli3(R)) or activator (Gli3(A)) depending upon cellular context. Previously, we have shown that Gli3(R) is required for the formation of mammary placodes #3 and #5. Here, we report that this early loss of Gli3 results in abnormal patterning of two critical regulators: Bmp4 and Tbx3, within the presumptive mammary rudiment (MR) #3 zone. We also show that Gli3 loss leads to failure to maintain mammary mesenchyme specification and loss of epithelial Wnt signaling, which impairs the later development of remaining MRs: MR#2 showed profound evagination and ectopic hairs formed within the presumptive areola; MR#4 showed mild invagination defects and males showed inappropriate retention of mammary buds in Gli3(xt/xt) mice. Importantly, mice genetically manipulated to misactivate Hh signaling displayed the same phenotypic spectrum demonstrating that the repressor function of Gli3(R) is essential during multiple stages of mammary development. In contrast, positive Hh signaling occurs during nipple development in a mesenchymal cuff around the lactiferous duct and in muscle cells of the nipple sphincter. Collectively, these data show that repression of Hh signaling by Gli3(R) is critical for early placodal patterning and later mammary mesenchyme specification whereas positive Hh signaling occurs during nipple development.

Dopamine and estradiol interact in the regulation of lactotroph cell proliferation and prolactin secretion. Ablation of the dopamine D2 receptor gene (Drd2(-/-)) in mice leads to a sexually dimorphic phenotype of hyperprolactinemia and pituitary hyperplasia, which is stronger in females. TGF-beta1 is a known inhibitor of lactotroph proliferation. TGF-beta1 is regulated by dopamine and estradiol, and it is usually down-regulated in prolactinoma experimental models. To understand the role of TGF-beta1 in the gender-specific development of prolactinomas in Drd2(-/-) mice, we compared the expression of different components of the pituitary TGF-beta1 system, including active cytokine content, latent TGF-beta-binding protein isoforms, and possible local TGF-beta1 activators, in males and females in this model. Furthermore, we evaluated the effects of dopamine and estradiol administration to elucidate their role in TGF-beta1 system regulation. The expression of active TGF-beta1, latent TGF-beta-binding protein isoforms, and several putative TGF-beta1 activators evaluated was higher in male than in female mouse pituitary glands. However, Drd2(-/-) female mice were more sensitive to the decrease in active TGF-beta1 content, as reflected by the down-regulation of TGF-beta1 target genes. Estrogen and dopamine caused differential regulation of several components of the TGF-beta1 system. In particular, we found sex- and genotype- dependent regulation of active TGF-beta1 content and a similar expression pattern for 2 of the putative TGF-beta1 activators, thrombospondin-1 and kallikrein-1, suggesting that these proteins could mediate TGF-beta1 activation elicited by dopamine and estradiol. Our results indicate that (1) the loss of dopaminergic tone affects the pituitary TGF-beta1 system more strongly in females than in males, (2) males express higher levels of pituitary TGF-beta1 system components including active cytokine, and (3) estradiol negatively controls most of the components of the system. Because TGF-beta1 inhibits lactotroph proliferation, we propose that the higher levels of the TGF-beta1 system in males could protect or delay the development of prolactinomas in Drd2(-/-) male mice.