The relationship between sonic Hedgehog signaling, cilia, and neural tube defects

Abstract

The Hedgehog signalling pathway is essential for many aspects of normal embryonic development, including formation and patterning of the neural tube. Absence of Shh ligand is associated with the midline defect holoprosencephaly, while increased Shh signalling is associated with exencephaly and spina bifida. To complicate this apparently simple relationship, mutation of proteins required for function of cilia often leads to impaired Shh signalling and to disruption of neural tube closure. In this manuscript, we review the literature on Shh pathway mutants and discuss the relationship between Shh signalling, cilia and neural tube defects.

Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development

“…A PCP-related pathway in which Cecr2 could influence polarity is ciliogenesis. Cilia defects, especially those with increased activity of the Shh pathway, are often associated with exencephaly (Murdoch and Copp, 2010). However, Cecr2 mutants do not have the other typical features of ciliogenesis mutants.…”

Role of the ANKMY2-FKBP38 Axis in Regulation of the Sonic Hedgehog (Shh) Signaling Pathway

“…Active Smo then signals to the cytoplasm, resulting in activation of the zinc finger transcription factors that control the output of the Shh pathway, which in vertebrates are the Gli proteins (Gli1, -2, and -3) (7). A unique feature of the vertebrate Shh pathway is that the primary cilium plays a central role in signal transduction (8,9), with the initial signaling events at the membrane taking place in this organelle. Ptch is located at the base of the primary cilium (10), and the binding of Shh to Ptch results in the activation of Smo and its recruitment to the cilium (11).…”

Le cil primaire, orchestrateur de la morphogenèse cérébrale

“…Ces cils baignent initialement dans la cavité amniotique, puis feront face ensuite à la cavité centrale du tube neural après le soulèvement et la fusion des bourrelets neuraux le long de la ligne médiane. [11]. Chez l'homme, des défauts équivalents conduisent à des anencéphalies, un signe clinique rare, décrit parfois chez des foetus atteints du syndrome de Meckel ou du syndrome acrocalleux [2].…”

“…Tulp3 -/-, 37 % pour la mutation Ftm -/-, 30 % pour la mutation Inpp5e -/-, ou encore 28 % chez les animaux Mks1 -/- [11]. De plus, le fond génétique influence considérablement la fréquence de ce phénotype, ce qui pourrait indiquer un déterminisme multifactoriel et/ou des sensibilités différentes aux subtiles variations stochastiques qui surviennent lors du développement.…”