Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway

The mammalian Sonic hedgehog (Shh) signalling pathway is essential for embryonic development and the patterning of multiple organs. Disruption or activation of Shh signalling leads to multiple birth defects, including holoprosencephaly, neural tube defects and polydactyly, and in adults results in tumours of the skin or central nervous system. Genetic approaches with model organisms continue to identify novel components of the pathway, including key molecules that function as positive or negative regulators of Shh signalling. Data presented here define Tulp3 as a novel negative regulator of the Shh pathway. We have identified a new mouse mutant that is a strongly hypomorphic allele of Tulp3 and which exhibits expansion of ventral markers in the caudal spinal cord, as well as neural tube defects and preaxial polydactyly, consistent with increased Shh signalling. We demonstrate that Tulp3 acts genetically downstream of Shh and Smoothened (Smo) in neural tube patterning and exhibits a genetic interaction with Gli3 in limb development. We show that Tulp3 does not appear to alter expression or processing of Gli3, and we demonstrate that transcriptional regulation of other negative regulators (Rab23, Fkbp8, Thm1, Sufu and PKA) is not affected. We discuss the possible mechanism of action of Tulp3 in Shh-mediated signalling in light of these new data

A Non-Contentious Account of Article III\u27s Domestic Relations Exception

Scholars and jurists have long debated the origins and current scope of the so-called domestic relations exception to Article III. Rooted in the perception that certain family law matters lie beyond the power of the federal courts, the exception was first articulated in the nineteenth-century decisional law of the Supreme Court and has perplexed observers ever since. Scholarly debate continues, despite the Court’s twentieth-century decision to place the exception firmly on statutory grounds in an effort to limit its potentially disruptive force. This Article offers a novel, historically grounded account of the domestic relations exception, connecting its origins to the Article III distinction between “cases” and “controversies.” Much domestic relations law fails to present a “controversy” within the meaning of Article III; the consensual nature of many status-altering acts (marriage, consensual divorce, adoption) forecloses a federal dispute-resolution role. But when federal courts hear “cases” arising under federal law, they have full power to exercise both contentious and (what Roman and civil lawyers refer to as) non-contentious jurisdiction. Our non-contentious account explains a range of puzzles, including why Article III courts can issue decrees at the core of the domestic relations exception when the matter at hand implicates federal law

[Y{2,6-(C5H4CH2)2C5H3N}(µ-OH)]2: a Dinuclear 5-ansa-Yttrocene Hydroxide containing the 2,6-dimethylenepyridyl Bridge

INORG. CHEM. COMM