Biology subjects

Nusspaumer, G.

Publications and source records attributed to Nusspaumer, G..

4 recordsLinked to original sources

bioRxiv2026

Network inference at single-cell resolution reveals morphoregulatory divergence and multilayered buffering in limb evolution

How changes in conserved developmental genetic programs contribute to morphological evolution remains poorly understood, particularly in non-conventional model species. Here, we combine single-cell transcriptomic and chromatin-accessibility profiling with cross-species label transfer and gene regulatory network inference to compare mouse and pig limb development. Our analyses identify broadly conserved cellular organization but discrete divergence in HOX-, FGF- and SHH-regulated programs. FGFR inhibition in mouse limb buds phenocopies the distal expansion of pig GREM1 expression, while altered SHH responses and anterior-posterior polarity converge on the PTCH1 regulatory landscape. Its functional dissection reveals degeneration of a limb regulatory module in artiodactyls, conservation of an additional distal enhancer, and extensive redundancy among cis-regulatory inputs. Allele-specific analyses further show that reduced Ptch1 dosage is buffered by transcriptional compensation. Together, these findings reveal how cis-regulatory and pathway-level robustness can accommodate distributed regulatory change while preserving developmental function, providing a mechanistic framework for the evolution of artiodactyl limb morphology.

developmental biology↗

bioRxiv2025

Functional architecture of cardiac TF regulatory landscapes in control of mammalian heart development

Congenital heart disease (CHD), the most common human birth defect, often results from disruptions in gene regulatory networks (GRNs) that control cardiac lineage specification and cell type identity during heart development. A conserved core set of cardiac transcription factors (TFs) orchestrates these processes through combinatorial interactions that are cell type-specific and tightly regulated across space and time. However, the genomic enhancer architecture that integrates upstream effectors to establish precise cardiac TF dosage and downstream transcriptional output remains largely unresolved. Here, we assessed the functional necessity of five developmental heart enhancer modules previously linked to the regulation of Gata4 and Hand2, core cardiac TFs exhibiting overlapping roles in myocardial and endocardial development. While individual enhancer deletions in mouse embryonic hearts revealed a surprising degree of transcriptional resilience, a subset of Gata4 enhancers proved indispensable for embryonic progression in a genetically compromised background. To achieve higher precision in cardiac cell type-specific enhancer prediction, we applied single-nucleus multiome profiling, enabling the delineation of cardiac cistromes underlying heart morphogenesis. By integrating this resource with deep learning applications, site-directed transgenesis, and chromatin conformation modeling, we mapped the cardiac enhancer repertoire and regulatory signatures that orchestrate Hand2 dynamics across distinct cardiac compartments and lineages. Genome editing further revealed an essential role for the Hand2-upstream regulatory interval (H2-URI) in transcriptional control of endocardial lineage effectors and, consequently, trabecular network formation and cardiac cushion patterning. Together our findings highlight substantial resilience in the cis-regulatory architectures governing cardiac TF dynamics and demonstrate that combinatorial integration of upstream lineage identities across modular enhancer landscapes establishes the cardiac cell type-specific programs driving heart morphogenesis. These results advance the reconstruction of cardiac GRNs and enhance the functional interpretation of CHD-associated variants.

developmental biology↗

bioRxiv2025

Neotenic transcriptomic features in the adult turquoise killifish brain

Aging is one of the main challenges facing modern society. Understanding the cellular processes that occur in the later stages of life is essential to address age-related diseases. Although aging is a global process that affects the entire body, the brain is one of the most sensitive organs and is affected by numerous degenerative diseases. In this study, we investigate cell types and genes that are particularly sensitive to the aging process. To this end, we performed a time-course single-cell RNAseq experiment series in the brain of the killifish, the vertebrate model with the shortest lifespan, which makes it an excellent model for aging studies. Our analysis reveals that non-glial progenitor cells are among those populations that change the most between young and old animals. Furthermore, we identify specialized stromal clusters that seem to support a primitive hematopoietic program in the brain, which is active only during the embryonic stages in other vertebrate species. Our results show that the expression of embryonic genes in the adult brain appears to be a general feature in killifish, and that several cell populations in the adult killifish brain show a higher level of similarity to the zebrafish embryonic populations than to adult ones. Our study suggests that adult killifish maintain a neotenic gene expression status in the brain that may help in sustaining their characteristic high proliferation and metabolic rates, as well as combat the detrimental effects of this high metabolism on cells, especially at advanced ages.

genomics↗

bioRxiv2023

The cellular landscape of the endochondral bone highlights its multipotent and immunomodulatory features during the transition to extrauterine life

The cellular complexity of the endochondral bone underlies its essential and pleiotropic roles during organismal life. While the adult bone has received significant attention, we still lack a deep understanding of the perinatal bone cellulome. Here, we have profiled the full composition of the murine endochondral bone at the single-cell level during the transition from fetal to newborn life and in comparison to the adult tissue, with particular emphasis on the mesenchymal compartment. The perinatal bone contains different fibroblastic clusters with blastema-like characteristics in organizing and supporting skeletogenesis, angiogenesis, and hematopoiesis. Our data also suggests dynamic inter- and intra-compartment interactions as well as a bone marrow milieu that seems prone to anti-inflammation, which we hypothesize is necessary to ensure the proper program of lymphopoiesis and the establishment of central and peripheral tolerance in early life. Our study provides an integrative roadmap for the future design of genetic and cellular functional assays to validate cellular interactions and lineage relationships within the perinatal bone.

cell biology↗