{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T12:46:58Z","timestamp":1791722818269,"version":"4.3.4"},"posted":{"date-parts":[[2025,9,21]]},"group-title":"Systems Biology","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,21]],"date-time":"2025-09-21T00:00:00Z","timestamp":1758412800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>During development, combinatorial signals modulate progenitor differentiation to build populations of diverse cell types. Classical deterministic fate-control circuits focus on stable commitment but do not explain how a diverse cell population is generated and tuned by signals. Here, using single-cell RNA-seq profiling of neural progenitor cells (NPCs) upon combinatorial signal inputs, we identify a candidate circuit-level mechanism for controlling cell type compositions through an annealed noise-driven switch. With 40 signaling conditions, we show that combinatorial signal inputs modulate the neuronal-glial population proportions following a simple log-linear model. Regulatory network models built by D-SPIN quantitatively capture cell state distribution shifts induced by signal combinations, and indicate a circuit model for the probabilistic fate specification by a differentiation switch with controlled transcriptional heterogeneity. Noise levels drive the system from highly plastic to committed states, allowing the relative level of signal inputs to shift population structures. The model further predicts an early bipotent state expressing lineage-specifying factors of both fates, which we verify in our single-cell profiling experiment and a mouse embryonic visual cortex development dataset. Our work identifies a design principle of noise-driven additive regulation in the logarithmic cell-fate probability space, providing a new strategy for population-level stem cell control.<\/jats:p>","DOI":"10.1101\/2025.09.20.677552","type":"posted-content","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:45:11Z","timestamp":1758501911000},"source":"Crossref","is-referenced-by-count":0,"title":["Tunable population diversity through a noise-driven differentiation switch"],"prefix":"10.64898","author":[{"given":"Jialong","family":"Jiang","sequence":"first","affiliation":[{"name":"Center for Studies in Physics and Biology, The Rockefeller University, New York, NY, 10065, USA"},{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, 91125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sisi","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, 91125, USA"},{"name":"Beckman Single-Cell Profiling and Engineering Center, California Institute of Technology, Pasadena, CA, 91125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong H.","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, 91125, USA"},{"name":"Beckman Single-Cell Profiling and Engineering Center, California Institute of Technology, Pasadena, CA, 91125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Tsou","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, 91125, USA"},{"name":"Beckman Single-Cell Profiling and Engineering Center, California Institute of Technology, Pasadena, CA, 91125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vickie","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, 91125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Rivaud","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, 91125, USA"},{"name":"Beckman Single-Cell Profiling and Engineering Center, California Institute of Technology, Pasadena, CA, 91125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Thomson","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, 91125, USA"},{"name":"Beckman Single-Cell Profiling and Engineering Center, California Institute of Technology, Pasadena, CA, 91125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026101105400875000_2025.09.20.677552v3.1","doi-asserted-by":"publisher","DOI":"10.1038\/35049541"},{"key":"2026101105400875000_2025.09.20.677552v3.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254927"},{"key":"2026101105400875000_2025.09.20.677552v3.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80853-3"},{"key":"2026101105400875000_2025.09.20.677552v3.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature09645"},{"key":"2026101105400875000_2025.09.20.677552v3.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.05.017"},{"key":"2026101105400875000_2025.09.20.677552v3.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2109729118"},{"key":"2026101105400875000_2025.09.20.677552v3.7","doi-asserted-by":"publisher","DOI":"10.1038\/nature06965"},{"key":"2026101105400875000_2025.09.20.677552v3.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.01.030"},{"key":"2026101105400875000_2025.09.20.677552v3.9","doi-asserted-by":"publisher","DOI":"10.1126\/science.1242366"},{"key":"2026101105400875000_2025.09.20.677552v3.10","doi-asserted-by":"publisher","DOI":"10.1038\/nature19348"},{"issue":"9","key":"2026101105400875000_2025.09.20.677552v3.11","doi-asserted-by":"crossref","first-page":"MSB178140","DOI":"10.15252\/msb.20178140","article-title":"Inheritance of oct4 predetermines fate choice in human embryonic stem cells","volume":"14","year":"2018","journal-title":"Molecular Systems Biology"},{"key":"2026101105400875000_2025.09.20.677552v3.12","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80860-0"},{"key":"2026101105400875000_2025.09.20.677552v3.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2007.10.006"},{"key":"2026101105400875000_2025.09.20.677552v3.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.04.020"},{"key":"2026101105400875000_2025.09.20.677552v3.15","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1996.0090"},{"key":"2026101105400875000_2025.09.20.677552v3.16","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.16-23-07599.1996"},{"key":"2026101105400875000_2025.09.20.677552v3.17","doi-asserted-by":"publisher","DOI":"10.1038\/nature09611"},{"key":"2026101105400875000_2025.09.20.677552v3.18","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)80048-9"},{"key":"2026101105400875000_2025.09.20.677552v3.19","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)00148-3"},{"issue":"13","key":"2026101105400875000_2025.09.20.677552v3.20","doi-asserted-by":"crossref","first-page":"4159","DOI":"10.1016\/j.cell.2026.04.028","article-title":"D-spin constructs regulatory network models from scrna-seq that reveal organizing principles of perturbation response","volume":"189","year":"2026","journal-title":"Cell"},{"key":"2026101105400875000_2025.09.20.677552v3.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09644-1"},{"key":"2026101105400875000_2025.09.20.677552v3.22","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-15-05820.1997"},{"key":"2026101105400875000_2025.09.20.677552v3.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808616105"},{"key":"2026101105400875000_2025.09.20.677552v3.24","doi-asserted-by":"publisher","DOI":"10.1101\/gad.10.24.3129"},{"key":"2026101105400875000_2025.09.20.677552v3.25","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.22047"},{"issue":"1","key":"2026101105400875000_2025.09.20.677552v3.26","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41467-017-02440-0","article-title":"Non-canonical wnt signaling regulates neural stem cell quiescence during homeostasis and after demyelination","volume":"9","year":"2018","journal-title":"Nature communications"},{"key":"2026101105400875000_2025.09.20.677552v3.27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M204527200"},{"key":"2026101105400875000_2025.09.20.677552v3.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0372-z"},{"key":"2026101105400875000_2025.09.20.677552v3.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.001"},{"key":"2026101105400875000_2025.09.20.677552v3.30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2216109120"},{"key":"2026101105400875000_2025.09.20.677552v3.31","doi-asserted-by":"crossref","unstructured":"Madeline G Andrews and Caroline A Pearson . Toward an understanding of glucose metabolism in radial glial biology and brain development. Life science alliance, 7(1), 2024.","DOI":"10.26508\/lsa.202302193"},{"issue":"5","key":"2026101105400875000_2025.09.20.677552v3.32","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.cmet.2020.08.015","article-title":"Glial metabolic rewiring promotes axon regeneration and functional recovery in the central nervous system","volume":"32","year":"2020","journal-title":"Cell metabolism"},{"key":"2026101105400875000_2025.09.20.677552v3.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401367101"},{"key":"2026101105400875000_2025.09.20.677552v3.34","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2001.0238"},{"key":"2026101105400875000_2025.09.20.677552v3.35","first-page":"124","article-title":"Btg1 is required to maintain the pool of stem and progenitor cells of the dentate gyrus and subventricular zone","volume":"6","year":"2012","journal-title":"Frontiers in neuroscience"},{"issue":"2","key":"2026101105400875000_2025.09.20.677552v3.36","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/s41592-019-0690-6","article-title":"Benchmarking algorithms for gene regulatory network inference from single-cell transcriptomic data","volume":"17","year":"2020","journal-title":"Nature methods"},{"key":"2026101105400875000_2025.09.20.677552v3.37","doi-asserted-by":"publisher","DOI":"10.1126\/science.1075762"},{"key":"2026101105400875000_2025.09.20.677552v3.38","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aag1796"},{"key":"2026101105400875000_2025.09.20.677552v3.39","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-016-2277-z"},{"key":"2026101105400875000_2025.09.20.677552v3.40","doi-asserted-by":"crossref","first-page":"662774","DOI":"10.3389\/fnmol.2021.662774","article-title":"The role of neurod genes in brain development, function, and disease","volume":"14","year":"2021","journal-title":"Frontiers in Molecular Neuroscience"},{"key":"2026101105400875000_2025.09.20.677552v3.41","doi-asserted-by":"publisher","DOI":"10.1101\/gad.403406"},{"key":"2026101105400875000_2025.09.20.677552v3.42","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2360"},{"key":"2026101105400875000_2025.09.20.677552v3.43","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80193-2"},{"key":"2026101105400875000_2025.09.20.677552v3.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2003.12.023"},{"issue":"1","key":"2026101105400875000_2025.09.20.677552v3.45","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/s41467-017-01203-1","article-title":"The wnt target sp5 negatively regulates wnt transcriptional programs in human pluripotent stem cells","volume":"8","year":"2017","journal-title":"Nature communications"},{"issue":"1","key":"2026101105400875000_2025.09.20.677552v3.46","doi-asserted-by":"crossref","first-page":"36050","DOI":"10.1038\/srep36050","article-title":"Lmo2 attenuates tumor growth by targeting the wnt signaling pathway in breast and colorectal cancer","volume":"6","year":"2016","journal-title":"Scientific reports"},{"key":"2026101105400875000_2025.09.20.677552v3.47","doi-asserted-by":"publisher","DOI":"10.1038\/35002131"},{"key":"2026101105400875000_2025.09.20.677552v3.48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0509547102"},{"key":"2026101105400875000_2025.09.20.677552v3.49","doi-asserted-by":"crossref","unstructured":"Mark I Freidlin and Alexander D Wentzell . Random perturbations of dynamical systems. In Random perturbations of dynamical systems. Springer, 1998.","DOI":"10.1007\/978-1-4612-0611-8"},{"issue":"3","key":"2026101105400875000_2025.09.20.677552v3.50","first-page":"291","article-title":"A scaling theory of bifurcations in the symmetric weak-noise escape problem","volume":"83","year":"1996","journal-title":"Journal of statistical physics"},{"issue":"12","key":"2026101105400875000_2025.09.20.677552v3.51","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/s41592-018-0229-2","article-title":"Deep generative modeling for single-cell transcriptomics","volume":"15","year":"2018","journal-title":"Nature methods"},{"key":"2026101105400875000_2025.09.20.677552v3.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.01.006"},{"key":"2026101105400875000_2025.09.20.677552v3.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.12.012"},{"key":"2026101105400875000_2025.09.20.677552v3.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.08.015"},{"issue":"7","key":"2026101105400875000_2025.09.20.677552v3.55","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/s41580-024-00709-z","article-title":"Cellular and molecular control of vertebrate somitogenesis","volume":"25","year":"2024","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"2026101105400875000_2025.09.20.677552v3.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.011"},{"key":"2026101105400875000_2025.09.20.677552v3.57","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.6.774"},{"key":"2026101105400875000_2025.09.20.677552v3.58","doi-asserted-by":"publisher","DOI":"10.1242\/dev.109678"},{"key":"2026101105400875000_2025.09.20.677552v3.59","doi-asserted-by":"publisher","DOI":"10.1038\/nature18320"},{"key":"2026101105400875000_2025.09.20.677552v3.60","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc6506"},{"key":"2026101105400875000_2025.09.20.677552v3.61","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0480-9"},{"key":"2026101105400875000_2025.09.20.677552v3.62","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2005990117"},{"key":"2026101105400875000_2025.09.20.677552v3.63","doi-asserted-by":"publisher","DOI":"10.1038\/nature04701"},{"issue":"13","key":"2026101105400875000_2025.09.20.677552v3.64","doi-asserted-by":"crossref","first-page":"4159","DOI":"10.1016\/j.cell.2026.04.028","article-title":"D-spin constructs regulatory network models from scrna-seq that reveal organizing principles of perturbation response","volume":"189","year":"2026","journal-title":"Cell"},{"issue":"12","key":"2026101105400875000_2025.09.20.677552v3.65","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/s41592-018-0229-2","article-title":"Deep generative modeling for single-cell transcriptomics","volume":"15","year":"2018","journal-title":"Nature methods"},{"issue":"2","key":"2026101105400875000_2025.09.20.677552v3.66","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/s41592-019-0690-6","article-title":"Benchmarking algorithms for gene regulatory network inference from single-cell transcriptomic data","volume":"17","year":"2020","journal-title":"Nature methods"},{"key":"2026101105400875000_2025.09.20.677552v3.67","doi-asserted-by":"publisher","DOI":"10.1126\/science.1075762"},{"key":"2026101105400875000_2025.09.20.677552v3.68","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aag1796"},{"key":"2026101105400875000_2025.09.20.677552v3.69","doi-asserted-by":"crossref","unstructured":"Mark I Freidlin and Alexander D Wentzell . Random perturbations of dynamical systems. InRandom perturbations of dynamical systems. Springer, 1998.","DOI":"10.1007\/978-1-4612-0611-8"},{"key":"2026101105400875000_2025.09.20.677552v3.70","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.01.006"},{"key":"2026101105400875000_2025.09.20.677552v3.71","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09644-1"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.09.20.677552","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T12:40:21Z","timestamp":1791722421000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.09.20.677552"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,21]]},"references-count":71,"URL":"https:\/\/doi.org\/10.1101\/2025.09.20.677552","relation":{},"subject":[],"published":{"date-parts":[[2025,9,21]]},"subtype":"preprint"}}