Multiple roles for lipids in the Hedgehog signalling pathway
ABSTRACT The identification of endogenous sterol derivatives that modulate the Hedgehog (Hh) signalling pathway has begun to suggest testable hypotheses for the cellular biological functions of Patched, and for the lipoprotein association of Hh. Progress in the field of intracellular sterol trafficking has emphasized how tightly the distribution of intracellular sterol is controlled, and suggests that the synthesis of sterol derivatives can be influenced by specific sterol-delivery pathways. The combination of this field with Hh studies will rapidly give us a more sophisticated understanding of both the Hh signal-transduction pathway and the cell biology of sterol metabolism.
SourceAvailable from: Natalia A Riobo-Del Galdo[Show abstract] [Hide abstract]
ABSTRACT: Obesity and diabetes represent key healthcare challenges of our day, affecting upwards of one billion people worldwide. These individuals are at higher risk for cancer, stroke, blindness, heart and cardiovascular disease, and to date, have no effective long-term treatment options available. Recent and accumulating evidence has implicated the developmental morphogen Hedgehog and its downstream signalling in metabolic control. Generally thought to be quiescent in adults, hedgehog is associated with several human cancers, and as such, has already emerged as a therapeutic target in oncology. Here, we attempt to give a comprehensive overview of the key signalling events associated with both canonical and non-canonical Hedgehog signalling, and highlight the increasingly complex regulatory modalities that appear to link Hedgehog and control metabolism. We highlight these key findings and discuss their impact for therapeutic development, cancer and metabolic disease.Seminars in Cell and Developmental Biology 05/2014; DOI:10.1016/j.semcdb.2014.05.007 · 5.97 Impact Factor
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ABSTRACT: In this study we show that postnatal development of cerebellar granule neurons (GNs) is defective in Npc1(-/-) mice. Compared to age-matched wild-type littermates, there is an accelerated disappearance of the external granule layer (EGL) in these mice. This is due to a premature exit from the cell cycle of GN precursors residing at the level of the EGL. As a consequence, the size of cerebellar lobules of these mice displays a 20%-25% reduction compared to that of age-matched wild-type mice. This size reduction is detectable at post-natal day 28 (PN28), when cerebellar GN development is completed while signs of neuronal atrophy are not yet apparent. Based on the analysis of EGL thickness and the determination of proliferating GN fractions at increasing developmental times (PN8-PN14), we trace the onset of this GN developmental defect during the second postnatal week. We also show that during this developmental time Shh transcripts undergo a significant reduction in Npc1(-/-) mice compared to age-matched wild-type mice. In light of the mitogenic activity of Shh on GNs, this observation further supports the presence of defective GN proliferation in Npc1(-/-) mice. A single injection of hydroxypropyl-β-cyclodextrin at PN7 rescues this defect, restoring the normal patterns of granule neuron proliferation and cerebellar lobule size. To our knowledge, these findings identify a novel developmental defect that was underappreciated in previous studies. This defect was probably overlooked because Npc1 loss-of-function does not affect cerebellar foliation and causes the internal granule layer and molecular layer to decrease proportionally, giving rise to a normally appearing, yet harmoniously smaller, cerebellum.Neurobiology of Disease 06/2014; 70. DOI:10.1016/j.nbd.2014.06.012 · 5.20 Impact Factor
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ABSTRACT: Apolipoproteins, the major components of lipoproteins, play physiological roles in lipoprotein metabolism. Contrary to the well-documented effects on plasma lipid, little is known about the function and regulation of Apolipoproteins during embryonic development. Here we have shown that apolipoprotein C1 (apoc1) gene is highly expressed in the yolk syncytial layer, a structure implicated in embryonic and larval nutrition. The apoc1 transcripts are also observed in the deep cell layer at the ventral and lateral region during gastrulation, and in the tail paraxial mesoderm during somitogenesis. By whole-mount in situ hybridization and quantified RT-RCR, we further demonstrate that apoc1 expression is induced by bone morphogenetic proteins (BMPs) signaling, while retinoic acid (RA) signaling suppresses the expression of BMP ligands and inhibits the BMP effect in this process.Gene 10/2014; DOI:10.1016/j.gene.2014.10.047 · 2.08 Impact Factor