Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling

141

199

Evolutionarily conserved hedgehog proteins orchestrate the patterning of embryonic tissues, and dysfunctions in their signaling can lead to tumorigenesis. In vertebrates, Sonic hedgehog (Shh) is essential for nervous system development, but the mechanisms underlying its action remain unclear. Early electrical activity is another developmental cue important for proliferation, migration, and differentiation of neurons. Here we demonstrate the interplay between Shh signaling and Ca 2+ dynamics in the developing spinal cord. Ca 2+ imaging of embryonic spinal cells shows that Shh acutely increases Ca 2+ spike activity through activation of the Shh coreceptor Smoothened (Smo) in neurons. Smo recruits a heterotrimeric GTP-binding protein-dependent pathway and engages both intracellular Ca 2+ stores and Ca 2+ influx. The dynamics of this signaling are manifested in synchronous Ca 2+ spikes and inositol triphosphate transients apparent at the neuronal primary cilium. Interaction of Shh and electrical activity modulates neurotransmitter phenotype expression in spinal neurons. These results indicate that electrical activity and second-messenger signaling mediate Shh action in embryonic spinal neurons.

Section: Discussionmentioning

confidence: 99%

Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord

Belgacem

Borodinsky

2011

141

199

“…Because of the established role for Hh signaling both in normal neural precursor cells (9,15,17,18) and in other brain tumors, such as medulloblastoma (19)(20)(21)(22), we postulated that the Hh pathway might play a role in transformation of this ventral PPC population. To test the functional and possibly oncogenic role of the Hh pathway in ventral pontine Olig2 + precursor cells, we used a genetic mouse model in which the Hh pathway is specifically up-regulated in Olig2 + cells.…”

Section: Resultsmentioning

confidence: 99%

Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma

Monje

Mitra

Freret

et al. 2011

283

300

Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG selfrenewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.Hedgehog pathway | cancer stem cells | brainstem glioma

“…Arguably, defects in the Hh pathway are currently the most directly associated with abnormal cilia function (48). Hh signaling is important for the development and patterning of numerous tissues, including the hypothalamus, and has critical roles during adult neurogenesis (49,50). Thus, obesity in congenital Bbs mutants could arise through mispatterning of the hypothalamus.…”

Section: Discussionmentioning

confidence: 99%

Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Berbari¹,

Pasek²,

Malarkey³

et al. 2013

Although primary cilia are well established as important sensory and signaling structures, their function in most tissues remains unknown. Obesity is a feature associated with some syndromes of cilia dysfunction, such as Bardet-Biedl syndrome (BBS) and Alström syndrome, as well as in several cilia mutant mouse models. Recent data indicate that obesity in BBS mutant mice is due to defects in leptin receptor trafficking and leptin resistance. Furthermore, induction of cilia loss in leptin-responsive proopiomelanocortin neurons results in obesity, implicating cilia on hypothalamic neurons in regulating feeding behavior. Here, we directly test the importance of the cilium as a mediator of the leptin response. In contrast to the current dogma, a longitudinal study of conditional Ift88 cilia mutant mice under different states of adiposity indicates that leptin resistance is present only when mutants are obese. Our studies show that caloric restriction leads to an altered anticipatory feeding behavior that temporarily abrogates the anorectic actions of leptin despite normalized circulating leptin levels. Interestingly, preobese Bbs4 mutant mice responded to the anorectic effects of leptin and did not display other phenotypes associated with defective leptin signaling. Furthermore, thermoregulation and activity measurements in cilia mutant mice are inconsistent with phenotypes previously observed in leptin deficient ob/ob mice. Collectively, these data indicate that cilia are not directly involved in leptin responses and that a defect in the leptin signaling axis is not the initiating event leading to hyperphagia and obesity associated with cilia dysfunction.