Grover, K. | Search bioRxiv

bioRxiv2024

Multistability and predominant double-positive states in a four node mutually repressive network: a case study of Th1/Th2/Th17/T-reg differentiation

Elucidating the emergent dynamics of complex regulatory networks enabling cellular differentiation is crucial to understand embryonic development and suggest strategies for synthetic circuit design. A well-studied network motif often driving cellular decisions is a toggle switch - a set of two mutually inhibitory lineage-specific transcription factors A and B. A toggle switch often enables two possible mutually exclusive states - (high A, low B) and (low A, high B) - from a common progenitor cell. However, the dynamics of networks enabling differentiation of more than two cell types from a progenitor cell is not well-studied. Here, we investigate the dynamics of four master regulators A, B, C and D inhibiting each other, thus forming a toggle tetrahedron. Our simulations show that a toggle tetrahedron predominantly allows for co-existence of six double positive or hybrid states where two of the nodes are expressed relatively high as compared to the remaining two - (high A, high B, low C, low D), (high A, low B, high C, low D), (high A, low B, low C, high D), (low A, high B, high C, low D), (low A, low B, high C, high D) and (low A, high B, low C, high D). Stochastic simulations showed state-switching among these phenotypes, indicating phenotypic plasticity. Finally, we apply our results to understand the differentiation of naive CD4+ T cells into Th1, Th2, Th17 and Treg subsets, suggesting Th1/Th2/Th17/Treg decision-making to be a two-step process. Our results reveal multistable dynamics and establish the stable co-existence of hybrid cell-states, offering a potential explanation for simultaneous differentiation of multipotent naive CD4+ T cells.

systems biology↗

bioRxiv2023

Developmental adaptation of rod photoreceptor number via photoreception in melanopsin (OPN4) retinal ganglion cells

Photoreception, a form of sensory experience, is essential for normal development of the mammalian visual system. Detecting photons during development is a prerequisite for visual system function - from visions first synapse at the cone pedicle and maturation of retinal vascular networks, to transcriptional establishment and maturation of cell types within the visual cortex. Consistent with this theme, we find that the lighting environment regulates developmental rod photoreceptor apoptosis via OPN4-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). Using a combination of genetics, sensory environment manipulations, and computational approaches, we establish a molecular pathway in which light-dependent glutamate release from ipRGCs is detected via a transiently expressed kainate receptor (GRIK3) in immature rods localized to the inner retina. Communication between ipRGCs and nascent inner retinal rods appears to be mediated by unusual hybrid neurites projecting from ipRGCs that sense light before eye-opening. These structures, previously referred to as outer retinal dendrites (ORDs), span the ipRGC-immature rod distance over the first postnatal week and contain the machinery for sensory detection (melanopsin, OPN4) and axonal/anterograde neurotransmitter release (Synaptophysin, and VGLUT2). Histological and computational assessment of human mid-gestation development reveal conservation of several hallmarks of an ipRGC-to-immature rod pathway, including displaced immature rods, transient GRIK3 expression in the rod lineage, and the presence of ipRGCs with putative neurites projecting deep into the developing retina. Thus, this analysis defines a retinal retrograde signaling pathway that links the sensory environment to immature rods via ipRGC photoreceptors, allowing the visual system to adapt to distinct lighting environments priory to eye-opening.

neuroscience↗