Developmental cell最新文献

Sprouting angiogenesis and blood vessel stabilization require precise coordination between endothelial cells (ECs) and pericytes. Bone Morphogenic Protein 9 (Bmp9), whose signaling through activin receptor-like kinase 1 (Alk1) is dysregulated in several diseases, was thought to regulate these processes by independently activating Notch target genes in an additive fashion with canonical Notch signaling. Here, through predictive computational modeling validated in mice, zebrafish, and human cell lines, we uncover that Bmp9 enhances Notch activity synergistically by upregulating Lunatic Fringe (Lfng) in ECs. Specifically, Bmp9-induced Lfng enhances Notch receptor activation, most strongly when Delta-like ligand 4 (Dll4) is also present. This Lfng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement during angiogenesis. Lfng also contributes to pericyte-driven vessel stabilization by mediating Jagged1 upregulation in Bmp9-stimulated ECs. In summary, Bmp9-upregulated Lfng enhances Dll4-Notch1 signaling in ECs and Jag1-Notch3 activation in pericytes, shaping angiogenic sprouting and stabilization outcomes.

Calcium (Ca) availability is vital for optimal plant growth and immune signaling, yet the underlying mechanisms remain elusive. Here, we reveal that Arabidopsis vacuolar H⁺-pyrophosphatase (AVP1)-regulated cytosolic inorganic pyrophosphate (PPi) homeostasis governs leaf growth by maintaining cellulose synthesis to suppress autoimmune activation upon Ca deficiency. Ca deficiency reduces the AVP1 abundance, while AVP1 eliminates excess cytosolic PPi, which impairs guanosine triphosphate-dependent microtubule assembly and reduces cellulose synthase 3-mediated cellulose synthesis. This cell-wall disruption activates isochorismate synthase 1-mediated salicylic acid production, triggering autoimmune responses and inhibiting new leaf growth. Enhancing PPi hydrolysis genetically improves plant growth tolerance to low Ca availability (low-Ca). The link between Ca-dependent PPi metabolic regulation, autoimmunity, and leaf growth is conserved in tomato, highlighting the broad relevance of AVP1 and PPi homeostasis in plant resilience. Our findings offer potential strategies for improving crop tolerance to nutrient-limited environments.

Although hypoxia-inducible factors (HIFs) are central regulators of cellular adaptation to oxygen and metabolic fluctuations in the mammalian brain, potential roles for HIF regulation during inhibitory neuron development are poorly understood. Here, we report that Nkx2.1-cre-driven conditional deletion of Hif1/2a in the medial ganglionic eminence (MGE) leads to reduced proliferation of Lhx6-positive interneuron precursors, whereas loss of von Hippel-Lindau (vHL), required for HIF degradation, drives increased precursor proliferation. Integrating single-cell transcriptomics, we identified HIF targets regulating proliferation and synaptogenesis. We also show that HIF1A directly activates glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B), encoding glutamate ionotropic receptor N-methyl-D-aspartate (NMDA) subunit 2B. In the adult HIF1 conditional knockout (cKO) cortex, we observed decreased numbers of parvalbumin (PV) interneurons and fewer GABAergic synapses and GRIN2B/Bassoon puncta on layer 2/3 excitatory neurons, resulting in attenuated long-term potentiation. These findings identify non-canonical roles for HIF signaling that are essential for PV interneuron production, GRIN2B expression, and cortical circuit maturation and function.