Biology subjects

Patel, J. H.

Publications and source records attributed to Patel, J. H..

5 recordsLinked to original sources

bioRxiv2025

ILC2s govern imprinting of alveolar macrophage-mediated immunity upon secondary helminth infection in the lung

Hookworm parasites migrate through the pulmonary system as part of their lifecycle, causing significant tissue damage that activates tissue-resident cell populations such as ILC2s. These cells drive type 2 immune responses critical for wound healing and the development of protective immunity. Macrophages, particularly monocyte-derived macrophages that seed the lung after infection, are central effectors of these responses and may be distinct from the tissue-resident populations they replace. However, the cellular and molecular factors governing the attrition of tissue-resident (TR) macrophages and their replacement remain poorly understood. We find that ILC2s and IL-4/IL-13-producing CD4+ T cells bi-directionally interact to regulate alveolar macrophage (AM) populations during infection. In the absence of these cells, type 2 immune responses are muted, leading to impaired anti-parasitic immunity in the lung during re-infection. This correlates with diminished expansion of type 2-polarized monocyte-derived alveolar macrophages (Mo-AMs), which are metabolically and transcriptionally distinct from TR-AMs. While Mo-AMs highly upregulated expression of Arg1, this was not essential for development of protective immunity in the lung. Concomitant with a more glycolytic metabolism, ILC2-induced Mo-AMs selectively upregulate arachidonate 15-lipoxygenase (Alox15), which promotes the capacity of macrophages to attack parasites in vitro. These results identify ILC2s as critical regulators of alveolar macrophage dynamics and important mediators of their function during helminth infection of the lung.

immunology↗

bioRxiv2025

Acvr2b receptors transduce all BMP signaling in the zebrafish gastrula and restrict Fibrodysplasia Ossificans Progressiva ACVR1-R206H signaling in a dose-dependent manner

BMP signaling drives dorsoventral (DV) axial patterning in vertebrates and invertebrates, with BMP dimers recruiting tetrameric receptor complexes to phosphorylate SMADs that activate target gene expression. In zebrafish DV patterning, Bmp2/7 heterodimers exclusively signal, assembling a receptor complex of two distinct type I receptors, Bmpr1 and Acvr1l, that canonically bind Bmp2 and Bmp7 ligands, respectively. Here, we tested if the two distinct classes of BMP type II receptors, Bmpr2 and Acvr2, also act in the gastrula signaling complex. We mutated all four acvr2a and acvr2b genes in the zebrafish and found maternal-zygotic depletion of Acvr2b receptors causes severe embryonic dorsalization, while bmpr2 genes are not expressed in the gastrula, indicating Acvr2b is the primary type II receptor transducing the BMP signal. Further, while phosphorylated Smad5 (pSmad5) was reduced throughout the early gastrula, unexpectedly, pSmad5 was nearly abrogated at the embryonic margin, where Nodal signaling is active in specifying the mesendoderm. We found that inhibiting Nodal signaling by depleting its co-receptor, Oep, in MZ-Acvr2b deficient embryos restored marginal pSmad5 to non-marginal levels, suggesting that Nodal competes with BMP for Acvr2a receptors at the margin. Further, we find that while Bmpr2 is not expressed in the gastrula, it can signal in the absence of Acvr2b, indicating that, unlike the type I receptor classes, the type II receptor classes do not uniquely function in the Bmp2/7 signaling complex. We further demonstrate that the ACVR1-R206H Fibrodysplasia Ossificans Progressiva human disease-causing mutant receptor, ACVR1-R206H, displays an increased sensitivity to Acvr2b dosage compared to wild-type Acvr1l, indicating that Acvr2b receptor availability restricts multiple modes of signaling in the gastrula.

developmental biology↗

bioRxiv2025

An IMPDH2 variant associated with neurodevelopmental disorder disrupts purine biosynthesis and somitogenesis

IMP dehydrogenase (IMPDH) controls a key regulatory node in purine biosynthesis. Gain-of-function mutations in human IMPDH2 are associated with neurodevelopmental disorders and neuromuscular symptoms including dystonia, but the developmental mechanisms underlying these defects are unknown. We previously showed that these mutants are insensitive to GTP inhibition and hypothesized that their hyperactivity would affect nucleotide metabolism in vivo. Here, we characterize the metabolic and developmental consequences of the neurodevelopmental disorder-associated IMPDH2 mutant, S160del, in Xenopus tropicalis. We show that expressing S160del but not WT human IMPDH2 disrupts purine pools and somitogenesis in the developing tadpole. We also show that S160del disrupts in vivo IMPDH filament assembly, a well-described IMPDH regulatory mechanism. Cryo-EM structures show that S160del disrupts filament assembly by destabilizing the dimerization of regulatory Bateman domains. Dimerization of Bateman domains and subsequent filament formation can be restored with a high affinity ligand, but this does not restore sensitivity to GTP inhibition, suggesting S160del also disrupts allostery of IMPDH2 filaments. This work demonstrates that the structural effects of patient IMPDH2 variants can cause disruptions both to nucleotide levels and to the normal development of sensorimotor structures, helping us better understand the physiological basis of disease in these patients. SIGNIFICANCE STATEMENTIMPDH2 is a critical enzyme for de novo purine biosynthesis, regulating the balance between adenine and guanine nucleotides. Under purine stress, it forms filaments that resist feedback inhibition by GTP. Patients with gain-of-function variants of this enzyme suffer from early-onset neuromotor symptoms including dystonia. Here, we express one gain-of-function variant of IMPDH2, S160del, in Xenopus tropicalis. S160del is particularly powerful for structural and developmental studies, as it impedes filament formation and also is insensitive to feedback inhibition by GTP. Here, we show S160del can perturb vertebrate development, metabolism, and filament formation in a dominant fashion. Insights from this work will open the door to a new suite of studies defining the function of purine metabolism in development and disease.

biochemistry↗

bioRxiv2024

Appendage regeneration requires IMPDH2 and creates a sensitized environment for enzyme filament formation

Regeneration of lost tissue requires biosynthesis of metabolites needed for cell proliferation and growth. Among these are the critical purine nucleotides ATP and GTP. The abundance and balance of these purines is regulated by inosine monophosphate dehydrogenase 2 (IMPDH2), which catalyzes the committing step of GTP synthesis. IMPDH2 assembles into filaments that resist allosteric inhibition under conditions of high GTP demand. Here we asked whether IMPDH2 is required in the highly proliferative context of regeneration, and whether its assembly into filaments takes place in regenerating tissue. We find that inhibition of IMPDH2 leads to impaired tail regeneration and reduced cell proliferation in the tadpole Xenopus tropicalis. We find that both endogenous and fluorescent fusions of IMPDH2 robustly assemble into filaments throughout the tadpole tail, and that the regenerating tail creates a sensitized condition for filament formation. These findings clarify the role of purine biosynthesis in regeneration and reveal that IMPDH2 enzyme filament formation is a biologically relevant mechanism of regulation in vertebrate regeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/605679v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1006d64org.highwire.dtl.DTLVardef@10ddf85org.highwire.dtl.DTLVardef@1cdc99eorg.highwire.dtl.DTLVardef@16fc4cb_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2021

Hif1α is required for Wnt regulated gene expression during Xenopus tropicalis tail regeneration

Regeneration of complex tissues is initiated by an injury-induced stress response, eventually leading to activation of developmental signaling pathways such as Wnt signaling. How early injury cues are interpreted and coupled to activation of these developmental signals and their targets is not well understood. Here, we show that Hif1, a stress induced transcription factor, is required for tail regeneration in Xenopus tropicalis. We find that Hif1 is required for regeneration of differentiated axial tissues, including axons and muscle. Using RNA-sequencing, we find that Hif1 and Wnt converge on a broad set of genes required for posterior specification and differentiation, including the posterior hox genes. We further show that Hif1 is required for transcription via a Wnt-responsive element, a function that is conserved in both regeneration and early neural patterning. Our findings indicate a regulatory role for Hif1 in Wnt mediated gene expression across multiple tissue contexts.

developmental biology↗