CREB Non-autonomously Controls Reproductive Aging through Hedgehog/Patched Signaling

Dev Cell. 2020 Jul 6;54(1):92-105.e5. doi: 10.1016/j.devcel.2020.05.023. Epub 2020 Jun 15.


Evolutionarily conserved signaling pathways are crucial for adjusting growth, reproduction, and cell maintenance in response to altered environmental conditions or energy balance. However, we have an incomplete understanding of the signaling networks and mechanistic changes that coordinate physiological changes across tissues. We found that loss of the cAMP response element-binding protein (CREB) transcription factor significantly slows Caenorhabditis elegans' reproductive decline, an early hallmark of aging in many animals. Our results indicate that CREB acts downstream of the transforming growth factor β (TGF-β) Sma/Mab pathway in the hypodermis to control reproductive aging, and that it does so by regulating a Hedgehog-related signaling factor, WRT-10. Overexpression of hypodermal wrt-10 is sufficient to delay reproductive decline and oocyte quality deterioration, potentially acting via Patched-related receptors in the germline. This TGF-β-CREB-Hedgehog signaling axis allows a key metabolic tissue to communicate with the reproductive system to regulate oocyte quality and the rate of reproductive decline.

Keywords: C. elegans; CREB; Hedgehog; TGF-beta; WRT-10; lifespan; oocyte quality; reproduction; reproductive span.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Aging / physiology
  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Oocytes / metabolism
  • Patched Receptors / genetics
  • Patched Receptors / metabolism*
  • Reproduction*
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism


  • Caenorhabditis elegans Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Hedgehog Proteins
  • Patched Receptors
  • Transforming Growth Factor beta