PITX1

Scientists reveal unprecedented insights into human limb development, including the many intricate processes that govern their formation. Human fingers and toes do not grow outward; instead, they form from within a larger foundational bud, as intervening cells recede to reveal the digits beneath. This is among many processes captured for the first time as scientists unveil a spatial cell atlas of the entire developing human limb, resolved in space and time. Researchers at the Wellcome Sanger Institute, Sun Yat-sen University, EMBL's European Bioinformatics Institute and collaborators applied cutting-edge single-cell and spatial technologies to create an atlas characterising the cellular landscape of the early human limb, pinpointing the exact location of cells. This study is part of the international Human Cell Atlas initiative to map every cell type in the human body, to transform understanding of health and disease. The atlas, published today (6 December) in Nature, provides an openly available resource that captures the intricate processes governing the limbs' rapid development during the early stages of limb formation. The atlas also uncovers new links between developmental cells and some congenital limb syndromes, such as short fingers and extra digits. Limbs are known to initially emerge as undifferentiated cell pouches on the sides of the body, without a specific shape or function. However after 8 weeks of development, they are well differentiated, anatomically complex and immediately recognisable as limbs, complete with fingers and toes. This requires a very rapid and precise orchestration of cells. Any small disturbances to this process can have a downstream effect, which is why variations in the limbs are among the most frequently reported syndromes at birth, affecting approximately one in 500 births globally. While limb development has been extensively studied in mouse and chick models, the extent to which they mirror the human situation remained unclear. However, advances in technology now enable researchers to explore the early stages of human limb formation. In this new study, scientists from the Wellcome Sanger Institute, Sun Yat-sen University, and their collaborators analysed tissues between 5 and 9 weeks of development. This allowed them to trace specific gene expression programs, activated at certain times and in specific areas, which shape the forming limbs. Special staining of the tissue revealed clearly how cell populations differentially arrange themselves into patterns of the forming digits. As part of the study, researchers demonstrated that certain gene patterns have implications for how the hands and feet form, identifying certain genes, which when disrupted, are associated with specific limb syndromes like brachydactyly -- short fingers -- and polysyndactyly -- extra fingers or toes. The team were also able to confirm that many aspects of limb development are shared between humans and mice. Overall, these findings not only provide an in-depth characterisation of limb development in humans but also critical insights that could impact the diagnosis and treatment of congenital limb syndromes. Professor Hongbo Zhang, senior author of the study from Sun Yat-sen University, Guangzhou, said: "Decades of studying model organisms established the basis for our understanding of vertebrate limb development. However, characterising this in humans has been elusive until now, and we couldn't assume the relevance of mouse models for human development. What we reveal is a highly complex and precisely regulated process. It is like watching a sculptor at work, chiselling away at a block of marble to reveal a masterpiece. In this case, nature is the sculptor, and the result is the incredible complexity of our fingers and toes." Dr Sarah Teichmann, senior author of the study from the Wellcome Sanger Institute, and co-founder of the Human Cell Atlas, said: "For the first time, we have been able to capture the remarkable process of limb development down to single cell resolution in space and time. Our work in the Human Cell Atlas is deepening our understanding of how anatomically complex structures form, helping us uncover the genetic and cellular processes behind healthy human development, with many implications for research and healthcare. For instance, we discovered novel roles of key genes MSC and PITX1 that may regulate muscle stem cells. This could offer potential for treating muscle-related disorders or injuries." This study is part of the Human Cell Atlas (HCA), an international collaborative consortium which is creating comprehensive reference maps of all human cells -- the fundamental units of life -- as a basis for understanding human health and for diagnosing, monitoring, and treating disease. The HCA is likely to impact every aspect of biology and medicine, propelling translational discoveries and applications and ultimately leading to a new era of precision medicine. These data sets are available for interactive analysis at:

A pioneering study has unveiled that the 3D organization of DNA can influence the progression of the aggressive brain tumor known as glioblastoma. Having identified the factors that glioblastoma uses to respond to neurons by growing and spreading, this discovery paves the way for further research into new treatments for brain tumors. A pioneering study at Umeå University, Sweden, has unveiled that the 3D organization of DNA can influence the progression of the aggressive brain tumour known as glioblastoma. Having identified the factors that glioblastoma uses to respond to neurons by growing and spreading, this discovery paves the way for further research into new treatments for brain tumours. "We have now identified the most important factors behind how the tumour responds to nerve cells, thus becoming more dangerous. These findings offer hope in our long-term battle against this difficult-to-treat cancer, for which the prognosis has not improved in decades," comments Silvia Remeseiro, Wallenberg fellow at WCMM, Assistant Professor at Umeå University, and lead author of the study. Glioblastoma is the most fatal type of brain tumour among adults and there is currently no curative treatment. Glioblastoma patients typically face a survival of roughly one year post-diagnosis. Even following current treatment regimes, which include surgery, radiotherapy and chemotherapy, a mere four per cent of patients are still alive five years after diagnosis. One possible way to understand and tackle this form of cancer is through DNA. It is already known that changes, mutations, in parts of DNA that do not contain genes can increase the risk of cancer and affect how genes function. This is because DNA contains so-called enhancers, "switches" that ensure that the right genes are turned-on in the right cells at the right time. A tight control of genes is crucial. If there are errors in these "switches" or abnormalities on how they contact the genes, changes in gene expression occur, which can eventually lead to cancer. A further step forward was taken when researchers discovered synaptic connections between nerve cells and brain tumours. Nerve cells can send electrical signals to brain tumour cells that make the tumour grow and spread. This recent study by Umeå researchers highlights that alterations in DNA structure and in enhancers, which in turn affect how genes are expressed, are crucial for the communication between neurons and tumour cells. It offers insights into how glioblastoma cells become more dangerous in response to the signals from the nerve cells. Using cells from glioblastoma patients and advanced techniques to analyse DNA structure and epigenetics, the researchers identified the key players central to this neuron-to-tumour communication, named SMAD3 and PITX1. These two proteins bind to and control the DNA switches that regulate gene expression. In experiments on both cell cultures and mice, it was possible to see how SMAD3 inhibition, together with the signals from the nerve cells, potentiates the tumour's ability to grow and spread. "We are optimistic that our discovery can guide efforts to attack glioblastoma by controlling how nerve cells and brain tumours interact. This would enable the development of new treatment strategies targeting this critical communication, which could hopefully improve the prognosis of glioblastoma patients," concludes Silvia Remeseiro.