Heather Wilson

Abstract Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements. Recently, we identified Remodelin, a small-molecule agent that leads to amelioration of HGPS cellular defects through inhibition of the enzyme N-acetyltransferase 10 (NAT10). Here, we show the preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances the healthspan in a Lmna G609G HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS.

New millipede specimens from the Paleozoic of Scotland are described, including Archidesmus macnicoli Peach, 1882, from the Lower Devonian (Lochkovian) Tillywhandland Quarry SSSI and three new taxa— Albadesmus almondi, Pneumodesmus newmani , and Cowiedesmus eroticopodus —from the mid Silurian (late Wenlock—early Ludlow) Cowie Formation at Cowie Harbour. Cowiedesmus eroticopodus new species is placed within the new Cowiedesmidae within the new order Cowiedesmida. Kampecaris tuberculata Brade-Birks from the Lower Devonian (Siegenian) of the Lanark Basin near Dunure is shown not to be a kampecarid myriapod, redescribed as Palaeodesmus tuberculata and placed order incertae sedis within Archipolypoda. Anthracodesmus macconochiei Peach is also redescribed and tentatively placed order incertae sedis within Archipolypoda. Archidesmus macnicoli, Albadesmus almondi , and Palaeodesmus tuberculata are each demonstrated to have broad sternites with laterally placed coxal sockets and paramedian pores containing paired valves. These pores are interpreted as having housed eversible vesicles. Some specimens of Archidesmus macnicoli and Cowiedesmus eroticopodus are male and have a pair of modified legs on trunk segment 8, identified as leg pairs 10 and 11, respectively. The presence of modified anterior legs restricted to segment 8 increases the range of variability known in modified appendage location in male millipedes and compounds existing uncertainty about using the presence of gonopods on trunk segment 7 as a synapomorphy of Helminthomorpha. An affinity between Archidesmida and Cowiedesmida is suggested based on possession of modified legs on segment 8 and Archidesmida + Cowiedesmida is placed along with Euphoberiida in Archipolypoda based on possession of free, broad sternites with bivalved paramedian pores and fused pleurotergites. The oldest known evidence of spiracles is demonstrated in Pneumodesmus newmani , proving that the oldest known millipedes were fully terrestrial.

showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.

During embryonic development, adult haematopoietic stem cells (HSCs) emerge preferentially in the ventral domain of the aorta in the aorta-gonad-mesonephros (AGM) region. Several signalling pathways such as Notch, Wnt, Shh and RA are implicated in this process, yet how these interact to regulate the emergence of HSCs has not previously been described in mammals. Using a combination of ex vivo and in vivo approaches, we report here that stage-specific reciprocal dorso-ventral inductive interactions and lateral input from the urogenital ridges are required to drive HSC development in the aorta. Our study strongly suggests that these inductive interactions in the AGM region are mediated by the interplay between spatially polarized signalling pathways. Specifically, Shh produced in the dorsal region of the AGM, stem cell factor in the ventral and lateral regions, and BMP inhibitory signals in the ventral tissue are integral parts of the regulatory system involved in the development of HSCs.

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.