Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis.

Organisms must appropriately allocate energetic resources between essential cellular processes to maintain homeostasis and in turn, maximize fitness. The nutritional and homeostatic regulators of energy homeostasis have been studied in detail; however, how developmental signals might impinge on these pathways to govern cellular metabolism is poorly understood. Here, we identify a non-canonical role for Hedgehog (Hh), a classic regulator of development, in maintaining intestinal lipid homeostasis in C. elegans . We find that expression of two Hh ligands, GRD-3 and GRD-4, is controlled by the LIN-29/EGR transcription factor in the hypodermis, where the Hh secretion factor CHE-14/Dispatched also facilitates non-cell autonomous Hh signaling. We demonstrate, using C. elegans and mouse hepatocytes, that Hh metabolic regulation does not occur through the canonical Hh transcription factor, TRA-1/GLI, but rather through non-canonical signaling that engages mTOR Complex 2 (mTORC2) in the intestine. Hh mutants display impaired lipid homeostasis, including reduced lipoprotein synthesis and fat accumulation, decreased growth, and upregulation of autophagy factors, mimicking loss of mTORC2. Additionally, we found that Hh inhibits p38 MAPK signaling in parallel to mTORC2 activation and that both pathways act together to modulate of lipid homeostasis. Our findings show a non-canonical role for Hedgehog signaling in lipid metabolism via regulation of core homeostatic pathways and reveal a new mechanism by which developmental timing events govern metabolic decisions.

CLAVATA Signaling Ensures Reproductive Development in Plants across Thermal Environments.

The ability to thrive in diverse environments requires that species maintain development and reproduction despite dynamic conditions. Many developmental processes are stabilized through robust signaling pathways that cooperatively ensure proper development.1 During reproduction, plants like Arabidopsis thaliana continuously generate flowers on growing indeterminate inflorescences.2 Flower primordia initiation and outgrowth depends on the hormone auxin and is robust across diverse environments.3-6 Here, we show that reproductive development under different thermal conditions requires the integration of multiple pathways regulating auxin-dependent flower production. In colder/ambient temperatures, the receptor complex CLAVATA2/CORYNE (CLV2/CRN) is necessary for continuous flower outgrowth during inflorescence development. CLV2/CRN signaling is independent of CLAVATA1 (CLV1)-related receptor signaling but involves the CLAVATA3 INSENSITIVE RECEPTOR KINASE (CIK) family co-receptors, with higher order cik mutant combinations phenocopying clv2/crn flower outgrowth defects. Developing crn inflorescences display reduced auxin signaling, and restoration of auxin biosynthesis is sufficient to restore flower outgrowth in colder and ambient temperatures. In contrast, at higher temperatures, both clv2/crn signaling and heat-induced auxin biosynthesis via YUCCA family genes are synergistically required to maintain flower development. Our work reveals a novel mechanism integrating peptide hormone and auxin signaling in the regulation of flower development across diverse thermal environments.

BAM1/2 receptor kinase signaling drives CLE peptide-mediated formative cell divisions in Arabidopsis roots.

Cell division is often regulated by extracellular signaling networks to ensure correct patterning during development. In Arabidopsis, the SHORT-ROOT (SHR)/SCARECROW (SCR) transcription factor dimer activates CYCLIND6;1 (CYCD6;1) to drive formative divisions during root ground tissue development. Here, we show plasma-membrane-localized BARELY ANY MERISTEM1/2 (BAM1/2) family receptor kinases are required for SHR-dependent formative divisions and CYCD6;1 expression, but not SHR-dependent ground tissue specification. Root-enriched CLE ligands bind the BAM1 extracellular domain and are necessary and sufficient to activate SHR-mediated divisions and CYCD6;1 expression. Correspondingly, BAM-CLE signaling contributes to the restriction of formative divisions to the distal root region. Additionally, genetic analysis reveals that BAM-CLE and SHR converge to regulate additional cell divisions outside of the ground tissues. Our work identifies an extracellular signaling pathway regulating formative root divisions and provides a framework to explore this pathway in patterning and evolution.