Biology subjects

Towers, M.

Publications and source records attributed to Towers, M..

8 recordsLinked to original sources

bioRxiv2026

Transforming avian to mammalian modes of digit patterning

How a conserved embryonic organiser--the Sonic hedgehog (Shh)-expressing Zone of Polarising Activity (ZPA)--generates diverse limb architectures in amniotes remains a central problem in evolutionary and developmental biology. The principal difference across species lies in the number of digits produced from ZPA tissue: two in mammals1, one in the chick leg2 and none in the chick wing2. Here we show that this divergence is governed by a Shh-p27Kip1 pathway operating in avian, but not mammalian ZPAs. In chick wing ZPA explants, attenuation of this pathway reveals an intrinsic digit-forming programme, enabling cells to self-organise signalling networks and generate digits after grafting into a host wing bud. Guided by these findings, we redirected the chick leg, which retains stem amniote digit identities, to follow a mammalian-like developmental trajectory. Precise temporal restriction of Shh signalling transforms chick legs into pentadactyl limbs with digit identities characteristic of mammals and their therapsid ancestors, with two digits arising from the ZPA. These findings establish a unifying framework for how Shh controls both digit number and identity across amniotes.

developmental biology↗

bioRxiv2026

Generation of human hindlimb/genital tubercle progenitors from pluripotent stem cells

The hindlimbs and genital tubercle arise from a bipotent progenitor population within the posterior lateral plate mesoderm (pLPM) and share common genetic programmes, reflecting their deep evolutionary homology. Perturbations of this shared developmental programme underlie several congenital conditions. Yet most insights into the divergence of pLPM fates come from traditional model organisms, emphasising the need for a human-based system. Here, we report the WNT-FGF-BMP-dependent differentiation of human pluripotent stem cells (hPSCs) into pLPM-derived hindlimb/genital tubercle mesenchymal progenitors (HGTps). We show that BMP signalling plays a pivotal role in driving transcriptomic changes reminiscent of the trunk-to-tail transition--a major reorganisation of the embryonic body plan that initiates pLPM/HGTp specification. We further show that retinoic acid signalling exerts a biphasic effect on LPM specification: early exposure blocks trunk-to-tail transition-like transcriptome changes, whereas late exposure enhances genital tubercle mesenchymal fate by suppressing alternative pLPM derivatives. Strikingly, differentiating genital tubercle mesenchyme self-organises with an overlying epithelium resembling in vivo counterparts. Through xenografting approaches, we show that human HGTp-derived spheroids contribute to the genital tubercle region of the chick embryo revealing their developmental potency. Collectively, our work establishes a platform for the reverse engineering and disease modelling of human HGTps.

developmental biology↗

bioRxiv2025

Role of IL10 signaling in the circadian control of host response to Influenza infection

We have previously demonstrated that the circadian clock regulates the host response to influenza A virus (IAV) infection, conferring a time-of-day-specific protection -infection at dawn resulted in a threefold increase in survival and reduced immunopathology compared to infection at dusk. While IL10 is well-known for its immunoregulatory function, its role in IAV remains unclear, with studies reporting both protective and detrimental effects. Given the diurnal rhythmicity of IL-10 receptor (Il10ra) expression in the lung, we investigated the contribution of IL-10 signaling to time-of-day-specific IAV protection. We found that blocking IL10 signaling abrogated the time of day protection, leading to increased immunopathology characterized by enhanced lymphocyte infiltration and global immune activation (transcriptomic analysis). Interestingly, while later, IL-10R blockade also eliminated the time-of-day difference in IAV outcomes, it improved the outcome of dusk-infected mice. Furthermore, natural killer (NK) cell depletion suppressed IL-10 levels in bronchoalveolar lavage, suggesting a role for NK cells in regulating IL-10 signaling. In conclusion, incorporating the circadian context has not only clarified the IL-10 role in IAV infection but also underscored the pivotal influence of circadian regulation on immune responses.

immunology↗

bioRxiv2023

Fgf signalling triggers an intrinsic mesodermal timer that determines the duration of limb patterning

Complex signalling between the apical ectodermal ridge (AER - a thickening of the distal epithelium) and the mesoderm controls limb patterning along the proximo-distal axis (humerus to digits). However, the essential requirement for AER-Fgf signalling during in vivo development makes it difficult to understand the exact roles that it fulfils. To overcome this barrier, we developed an amenable ex vivo chick wing tissue explant system that faithfully replicates in vivo parameters. Using inhibition experiments and RNA-sequencing, we identify a transient role for Fgfs in triggering the distal patterning phase. Fgfs are then dispensable for the maintenance of an intrinsic mesodermal transcriptome, which controls proliferation/differentiation timing and the duration of patterning. We also uncover additional roles for Fgf signalling in maintaining AER-related gene expression and in suppressing myogenesis. We describe a simple logic for limb patterning duration, which is potentially applicable to other systems, including the main body axis.

developmental biology↗

bioRxiv2022

A neuroepithelial wave of BMP signalling drives anteroposterior specification of the tuberal hypothalamus

The tuberal hypothalamus houses several major hypothalamic nuclei, dozens of transcriptionally distinct cell types, and clinically relevant cell populations implicated in obesity and related metabolic disorders. Building on recent advances in the field, here we draw upon transcriptional, signalling, and fate mapping analyses of chicken embryos and neuroepithelial explants to analyze tuberal hypothalamic development. We show that a wave of BMP signalling sweeps through early floor plate-like progenitors overlying prospective Rathkes pouch as they track anteriorly. The timing of BMP signalling correlates with cell fate, with anterior tuberal specification complete by Hamilton-Hamburger (HH) stage 10 but posterior tuberal progenitors requiring BMPs after this point. scRNA-Seq profiling of FGF10-expressing cells, a proxy for cells with active BMP signalling, through HH8-21 reveals transcriptional differences that may underlie their differing response to BMPs, and the switch from neuroepithelial progenitors to stem-like radial glial cells. This study provides an integrated account of the development of the tuberal hypothalamus.

developmental biology↗

bioRxiv2021

Developmental timing scales wing patterning between avian species

A fundamental question in biology is how species-specific rates of embryonic development are controlled in differently sized species. To address this problem, we compared wing development in the quail and the larger chick. We reveal that pattern formation (humerus to digits) is faster in the quail wing as determined by the earlier activation of 5 Hox genes, termination of developmental organisers (Shh and Fgf8) and the laying down of the skeleton (Sox9). Using interspecies tissue grafts, we show that developmental timing can be reset during a critical window in which retinoic acid signalling is active. Accordingly, retinoic acid can switch developmental timing between the quail and chick, and also between the chick and the larger turkey. We show that the incremental growth rate is equivalent between all three species, suggesting that differences in the expansion of the skeletal pattern are governed primarily by the tempo of development. Our findings have implications for how development is timed both within and between different species.

developmental biology↗

bioRxiv2019

A positional information gradient of sonic hedgehog is required for flight feather formation in avian wings

Flight is a triumph of evolution that enabled the radiation and success of birds. A crucial step was the development of forelimb flight feathers that may have evolved for courtship or territorial displays in ancestral theropod dinosaurs. Classical tissue recombination experiments performed in the chick embryo provide evidence that signals operating during early limb development specify the position and identity of feathers. Here we show that a positional information gradient of Sonic hedgehog (Shh) signalling in the embryonic chick wing bud specifies the pattern of adult flight feathers in a defined spatial and temporal sequence that reflects their different identities. We reveal that the Shh signalling gradient is interpreted into specific patterns of flight feather-associated gene expression. Our data suggests that flight feather evolution involved the co-option of the pre-existing digit patterning mechanism and therefore uncovers an embryonic process that played a fundamental step in the evolution of avian flight.

developmental biology↗

bioRxiv2018

An intrinsic cell cycle timer terminates limb bud outgrowth

The longstanding view of how proliferative outgrowth terminates following the patterning phase of limb development involves the breakdown of reciprocal extrinsic signalling between the mesenchyme and the overlying epithelium (e-m signalling). However, by grafting mesenchyme cells from late stage chick wing buds to an early epithelial environment we show that this mechanism is not required. RNA sequencing reveals that mesenchyme cells terminate growth by an intrinsic cell cycle timer in the presence of e-m signalling. In this process, e-m signalling is required permissively to allow the intrinsic cell cycle timer to run its course. We provide evidence that a temporal switch from BMP antagonism to BMP signalling controls the intrinsic cell cycle timer during limb outgrowth. Our findings have general implications for other patterning systems in which extrinsic signals and intrinsic timers are integrated.

developmental biology↗