Thyroid hormone triggers the developmental loss of axonal regenerative capacity via thyroid hormone receptor α1 and krüppel-like factor 9 in Purkinje cells

Abstract

Neurons in the CNS of higher vertebrates lose their ability to regenerate their axons at a stage of development that coincides with peak circulating thyroid hormone (T 3 ) levels. Here, we examined whether this peak in T 3 is involved in the loss of axonal regenerative capacity in Purkinje cells (PCs). This event occurs at the end of the first postnatal week in mice. Using organotypic culture, we found that the loss of axon regenerative capacity was triggered prematurely by early exposure of mouse PCs to T 3 , whereas it was delayed in the absence of T 3 . Analysis of mutant mice showed that this effect was mainly mediated by the T 3 receptor α1. Using gain-and loss-of-function approaches, we also showed that Krüppel-like factor 9 was a key mediator of this effect of T 3 . These results indicate that the sudden physiological increase in T 3 during development is involved in the onset of the loss of axon regenerative capacity in PCs. This loss of regenerative capacity might be part of the general program triggered by T 3 throughout the body, which adapts the animal to its postnatal environment.axon regeneration | cerebellum | neural development | lentiviral vectors

The Glucocorticoid Receptor and KLF15 Regulate Gene Expression Dynamics and Integrate Signals through Feed-Forward Circuitry

“…Kruppel-like factors are increasingly recognized as important mediators of vital physiologic processes and are frequently regulated by nuclear receptors (45)(46)(47)(48). Relatively little is known about how KLF family members achieve transcriptional specificity, as the information content provided by their preferred DNA binding sequences, the CACCC box and variants (49,50), is relatively limited.…”

Bone-brain crosstalk and potential associated diseases

“…These data depict a mechanism whereby FSH antagonizes sex steroid action in bone targeting osteoclasts and up-regulating bone mass accrual [65] (Figure 1). Second, prolactin (PRL), a small peptide hormone secreted by the anterior pituitary gland [66], might also directly enhance osteoclast activity, and consequently bone turnover [67][68][69] (Figure 1). Third, the primitive mammalian neurohypophyseal hormone, oxytocin (OT) [66], stimulates osteoblast differentiation by up-regulating BMP-2 expression and osteoclast formation through the activation of NF-κB and MAP kinase signaling [66] (Figure 1).…”

“…Second, prolactin (PRL), a small peptide hormone secreted by the anterior pituitary gland [66], might also directly enhance osteoclast activity, and consequently bone turnover [67][68][69] (Figure 1). Third, the primitive mammalian neurohypophyseal hormone, oxytocin (OT) [66], stimulates osteoblast differentiation by up-regulating BMP-2 expression and osteoclast formation through the activation of NF-κB and MAP kinase signaling [66] (Figure 1). Lastly, using pharmacological, genetic and in vitro assays, it was shown that argininevasopressin (AVP), a hormone secreted by the posterior pituitary gland, decreases osteoblast proliferation while increasing osteoclastic activity through its receptor Avpr1 and Avpr2 [70] (Figure 1).…”

Rôle de l’hormone thyroïdienne T3 dans la régénération axonale chez les vertébrés supérieurs

“…De façon intéres-sante, chez les amphibiens comme le xénope, la perte de capacité régénéra-tive des neurones se produit juste après la métamorphose [4], qui est elle-même déclenchée par la T3. Dans le cadre d'un travail récemment publié dans les Proceedings of the National Academy of Sciences of USA, nous avons cherché à savoir si la T3 pouvait être impliquée dans la perte des capacités régénéra-tives axonales au cours du développe-ment d'un type de neurones, les cellules de Purkinje du cervelet [5]. Nous avons utilisé un modèle de culture organotypique, permettant d'isoler une région cérébrale tout en conservant une grande partie de la structure du tissu et les interactions cellulaires qui s'y produisent.…”

“…Une des modulations possible de ce programme de maturation cérébrale découle de la régulation autonome du taux de T3 cérébrale. On sait, en effet, que le taux intracérébral de T3 la cellule de Purkinje [5]. Mais le rôle de la T3 dans les cellules nerveuses ne se limite pas à cette fonction, car l'hormone participe, notamment, au déclenche-ment de la myélinisation [6].…”