Biology subjects

Headon, D. J.

Publications and source records attributed to Headon, D. J..

5 recordsLinked to original sources

bioRxiv2026

A frameshift mutation in PRICKLE1 causes skeletal dysplasia in Cheviot sheep

Skeletal dysplasias can occur in animals, including humans, and are attributed to both environmental and genetic causes. As our understanding of the distinguishing phenotypes of different skeletal dysplasias improves, alongside elucidation of the mechanisms and genetic networks that contribute to skeletal development, identifying and controlling genetic mutations in livestock populations has become increasingly possible, including approaches beyond selective breeding alone. Within Scotland an 'achondroplasia' syndrome that was first described in the South Country Cheviot breed of sheep (OMIA 000004-9940), has continued to occur periodically within the same geographical locations, despite culling of affected lambs over many decades. Affected lambs exhibit rounded heads, short legs, a loss of hooves, abnormal stance and short twisted tails. As the condition has been observed in flocks and as progeny from specific ram and ewe matings, and cases have been co-twinned to normal siblings, this suggests a syndrome caused by a recessive genetic condition rather than environmental factors. Through homozygosity mapping and whole genome sequence analyses, we identified a 10 bp deletion in the open reading frame of the PRICKLE1 gene that encodes prickle planar cell polarity protein 1 and is essential for normal vertebrate embryonic development. We identified additional phenotypes present in affected lambs, including a loss of phalanges, neural tube defects, vertebral and articular chondrocyte defects, hair orientation differences and polycystic kidneys, consistent with a loss of PRICKLE1 function based on comparisons to mouse mutant lines. These findings enabled the development of a simple DNA test for the identified PRICKLE1 mutation that was made commercially available to facilitate the elimination of this genetic disease from sheep flocks.

genetics↗

bioRxiv2025

FuChi: A cell cycle biosensor for investigating cell-cycle kinetics during avian development.

The ability to monitor the proliferative status of live cells both in vitro and in vivo over time has revolutionised our understanding of development, growth and disease. This was first made possible by fluorescent ubiquitination-based cell cycle indicator (Fucci) technology, which distinguishes specific cell cycle phases through the reciprocal degradation of fluorescently tagged, truncated forms of human CDT1 and GMNN proteins. Fucci genetic systems have been successfully implemented in transgenic mice, zebrafish, and axolotls. To date, no viable, stably expressing Fucci line has been developed in an avian species. Although a range of continuously improving Fucci constructs have been developed in recent years, existing in vivo Fucci models remain limited because they rely on older reporter technology that fails to distinguish cells in S, G2, and M phases or to label cells in early G1. As a result, these models can be challenging to interpret and their utility for continuous cell tracking and precise analysis of cell-cycle dynamics is limited. Here, we introduce FuChi, a multicistronic Fucci-expressing chicken line incorporating a newly optimised reporter construct composed of an mCerulean-tagged Histone H1.0 linker protein fused via a self-cleaving 2A peptide to the tandem Fucci(CA) cell cycle biosensor, with additional epitope tags included for detection in fixed tissues. We show that this system accurately discriminates and permits tracking of cells in G1, S, G2, and M phases both in vitro and in vivo, enabling faithful visualisation of cell cycle status in intact tissues and organs. Using FuChi embryos, we mapped proliferation dynamics across developing tissues, analysed cell cycle states of migrating cells, and performed live imaging of early embryos. These latter experiments revealed that transition from S phase may be a key morphogenetic event during gastrulation as mesendoderm cells egress from the primitive streak to form embryonic structures including the prechordal plate. Pairing this advanced reporter with the intrinsic experimental advantages of the chicken embryo positions FuChi as a premier in vivo system for studying cell-cycle kinetics in development, delivering clear technological improvements over current Fucci models. FuChi chickens provide a powerful new resource for studying embryonic development, organ growth, tissue homeostasis, disease processes, and infection responses.

developmental biology↗

bioRxiv2024

Characterisation of human hair follicle development

Humans have a characteristic distribution of hair across the body. Visible, relatively long and thick terminal hair fibres are present on the scalp and eyebrows in childhood, and are stimulated to grow on other parts of the body, such as the beard and armpits, by hormones during puberty. The short and fine vellus hairs, in contrast, are not readily visible and cover most of the body, including the face. Here we report quantification of the timing and characteristics of hair follicle development in human embryogenesis, from gestational weeks 8 to 19, and compare this to mouse hair follicle development. We find that human hair follicles develop first on the head, where we identify several distinct initiation sites, followed by the torso. Although terminal and vellus hair follicles have clear differences in the adult, both hair types initially develop from placodes and dermal condensates of similar size. Once their development is initiated, we find that human hair follicles grow and mature at the same rate, regardless of anatomical location, but have different density at different body sites. These findings suggest that regional hair differences in human skin, such as the distinction between scalp and forehead, are largely caused by processes acting after the initial hair follicle morphogenesis. Efforts to understand the evolution of human hairlessness should, therefore, focus on genetic and cellular events that take place after hair follicle morphogenesis. Finally, we compared human skin appendages, including eccrine sweat glands, with those in mouse. We found that molecular markers, such as EDA, EDAR, SOX2 and WNT pathway components, are broadly similar in expression between both species, although specific differences do exist. Together with comparison of morphology and gene expression, these results support the use of embryonic mouse primary hair follicles as a model for human hair follicle development.

developmental biology↗

bioRxiv2023

Newly born mesenchymal cells disperse through a rapid mechanosensitive migration

Embryonic mesenchymal cells are dispersed within an extracellular matrix but can coalesce to form condensates with key developmental roles. Cells within condensates undergo fate and morphological changes, and induce cell fate changes in nearby epithelia to produce structures including hair follicles, feathers or intestinal villi. Here, by imaging of mouse and chicken embryonic skin, we find that mesenchymal cells undergo much of their dispersal in early interphase, in a stereotyped process of displacement driven by three hours of rapid and persistent migration, followed by a long period of low motility. The cell division plane and the elevated migration speed and persistence of newly born mesenchymal cells are mechanosensitive, aligning with tension in the tissue. This early G1 migratory behaviour disperses mesenchymal cells and allows the daughters of recent divisions to travel long distances to enter dermal condensates, demonstrating an unanticipated effect of a cell cycle sub-phase on core mesenchymal behaviour. HighlightsO_LIAfter mesenchymal cell division the speed and persistence of daughter cell migration is elevated for 180 minutes C_LIO_LIMesenchymal cell division and migration are directed by tissue tension C_LIO_LINewly born mesenchymal cells are uniquely responsive to tissue strain C_LIO_LINewly born mesenchymal cells are preferentially recruited to dermal condensates C_LIO_LIIncreased dispersal of newly born cells enables long distance travel to dermal condensates C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/525849v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@c69b4dorg.highwire.dtl.DTLVardef@fe0295org.highwire.dtl.DTLVardef@5b9f61org.highwire.dtl.DTLVardef@13ca1aa_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2019

Characterisation of a second gain of function EDAR variant, encoding EDAR380R, in East Asia

EDAR is a TNF receptor family member with roles in the development and growth of hair, teeth and glands. A derived allele of EDAR, single nucleotide variant rs3827760, encodes EDAR370A, a receptor with more potent signalling effects than the ancestral EDAR370V. This allele of rs3827760 is at very high frequency in modern East Asian and Native American populations as a result of ancient positive selection and has been associated with straighter, thicker hair fibres, alteration of tooth and ear shape, reduced chin protrusion and increased fingertip sweat gland density. Here we report the characterisation of another SNV in EDAR, rs146567337, encoding EDAR380R. The derived allele of this SNV is at its highest global frequency, of up to 5%, in populations of southern China, Vietnam, the Philippines, Malaysia and Indonesia. Using haplotype analyses, we find that the rs3827760 and rs146567337 SNVs arose on distinct haplotypes and that rs146567337 does not show the same signs of positive selection as rs3827760. From functional studies in cultured cells, we find that EDAR380R displays increased EDAR signalling output, at a similar level to that of EDAR370A. The existence of a second SNV with partly overlapping geographic distribution, the same in vitro functional effect and similar evolutionary age as the derived allele of rs3827760, but of independent origin and not exhibiting the same signs of strong selection, suggests a northern focus of positive selection on EDAR function in East Asia.

genetics↗