About

Roeland Nusse is a professor in the field of Developmental Biology at Stanford University. His research focus is on developmental biology, contributing to the understanding of biological processes related to development. As a faculty member within the Human Biology program, he is involved in teaching and research activities that explore fundamental aspects of biology and development.

Research topics

• Cell biology
• Biology
• Computational biology
• Genetics
• Biochemistry
• Endocrinology

Selected publications

• APEX2-Mediated Proximity Labeling of Wnt Receptor Interactors Upon Pathway Activation

  PubMed · 2023-03-21 · 1 citations

  articleOpen accessSenior author

  The Wnt signaling pathway regulates metazoan development, tissue homeostasis, and regeneration. Many outstanding questions in Wnt signal transduction revolve around the molecular events immediately following Wnt-receptor interactions. To identify binding partners of the Wnt receptor Frizzled 7 (Fzd7) upon pathway activation, we tagged Fzd7 with APEX2, an enzyme that allows biotinylation of proximal interactors with high temporal and spatial resolution. Upon confirming proper localization and signaling activity of APEX2-tagged Fzd7, we labeled proximal interactors of Fzd7 with or without Wnt3a stimulation. Mass spectrometry analysis of biotinylated interactors identified several known Wnt pathway proteins. Top interactors enriched upon Wnt treatment were involved in actin cytoskeleton regulation, vesicle trafficking, or phospholipid modification. Proteins enriched in the Wnt-activated Fzd7 interactome that are without established roles in Wnt signaling warrant further examination.

  PublisherOA PDFDOI

• WNT signaling in pre-granulosa cells is required for ovarian folliculogenesis and female fertility

  Development · 2021-04-24 · 101 citations

  articleOpen access

  In mammalian ovaries, immature oocytes are reserved in primordial follicles until their activation for potential ovulation. Precise control of primordial follicle activation (PFA) is essential for reproduction, but how this is achieved is unclear. Here, we show that canonical wingless-type MMTV integration site family (WNT) signaling is pivotal for pre-granulosa cell (pre-GC) activation during PFA. We identified several WNT ligands expressed in pre-GCs that act in an autocrine manner. Inhibition of WNT secretion from pre-GCs/GCs by conditional knockout (cKO) of the wntless (Wls) gene led to female infertility. In Wls cKO mice, GC layer thickness was greatly reduced in growing follicles, which resulted in impaired oocyte growth with both an abnormal, sustained nuclear localization of forkhead box O3 (FOXO3) and reduced phosphorylation of ribosomal protein S6 (RPS6). Constitutive stabilization of β-catenin (CTNNB1) in pre-GCs/GCs induced morphological changes of pre-GCs from a squamous into a cuboidal form, though it did not influence oocyte activation. Our results reveal that canonical WNT signaling plays a permissive role in the transition of pre-GCs to GCs, which is an essential step to support oocyte growth.

  PublisherDOI

• Running Against the Wnt: How Wnt/β-Catenin Suppresses Adipogenesis

  Frontiers in Cell and Developmental Biology · 2021 · 137 citations

  Senior authorCorresponding
  • Cell biology
  • Biology
  • Endocrinology

  Mesenchymal stem cells (MSCs) give rise to adipocytes, osteocytes, and chondrocytes and reside in various tissues, including bone marrow and adipose tissue. The differentiation choices of MSCs are controlled by several signaling pathways, including the Wnt/β-catenin signaling. When MSCs undergo adipogenesis, they first differentiate into preadipocytes, a proliferative adipocyte precursor cell, after which they undergo terminal differentiation into mature adipocytes. These two steps are controlled by the Wnt/β-catenin pathway, in such a way that when signaling is abrogated, the next step in adipocyte differentiation can start. This sequence suggests that the main role of Wnt/β-catenin signaling is to suppress differentiation while increasing MSC and preadipocytes cell mass. During later steps of MSC differentiation, however, active Wnt signaling can promote osteogenesis instead of keeping the MSCs undifferentiated and proliferative. The exact mechanisms behind the various functions of Wnt signaling remain elusive, although recent research has revealed that during lineage commitment of MSCs into preadipocytes, Wnt signaling is inactivated by endogenous Wnt inhibitors. In part, this process is regulated by histone-modifying enzymes, which can lead to increased or decreased Wnt gene expression. The role of Wnt in adipogenesis, as well as in osteogenesis, has implications for metabolic diseases since Wnt signaling may serve as a therapeutic target.

  PublisherOA PDFDOI

• WNT signaling in pre-granulosa cells is required for ovarian folliculogenesis and female fertility

  Institutional Repositories DataBase (IRDB) · 2021-04-29

  articleOpen accessSenior author

  In mammalian ovaries, immature oocytes are reserved in primordial follicles until their activation for potential ovulation. Precise control of primordial follicle activation (PFA) is essential for reproduction, but how this is achieved is unclear. Here, we show that canonical wingless-type MMTV integration site family (WNT) signaling is pivotal for pre-granulosa cell (pre-GC) activation during PFA. We identified several WNT ligands expressed in pre-GCs that act in an autocrine manner. Inhibition of WNT secretion from pre-GCs/GCs by conditional knockout (cKO) of the wntless (Wls) gene led to female infertility. In Wls cKO mice, GC layer thickness was greatly reduced in growing follicles, which resulted in impaired oocyte growth with both an abnormal, sustained nuclear localization of forkhead box O3 (FOXO3) and reduced phosphorylation of ribosomal protein S6 (RPS6). Constitutive stabilization of β-catenin (CTNNB1) in pre-GCs/GCs induced morphological changes of pre-GCs from a squamous into a cuboidal form, though it did not influence oocyte activation. Our results reveal that canonical WNT signaling plays a permissive role in the transition of pre-GCs to GCs, which is an essential step to support oocyte growth.

  Publisher

• Self-activation of Wnt signaling in pre-granulosa cells is required for ovarian folliculogenesis

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-10-21

  preprintOpen access

  Summary In mammalian ovaries, immature oocytes are reserved in primordial follicles. Precise control of primordial follicle activation (PFA) is a prerequisite for proper reproduction. Although Wnt signaling is thought to be involved in folliculogenesis, the timing and function of Wnt activity remain unclear. Here we show that canonical Wnt signaling is pivotal for the differentiation of pre-granulosa cells (pre-GCs) and subsequent oocyte maturation during PFA. We identified several Wnt ligands expressed in pre-GCs that cell-autonomously function via canonical Wnt activity. Inhibition of Wnt ligand secretion from pre-GCs/GCs led to infertility due to impaired pre-GC differentiation, whereas constitutive stabilization of β-catenin induced thickening of the pre-GCs. Our data support a two-step model of PFA in which self-activation of Wnt signaling promotes the transition of pre-GCs to GCs, and mature GCs then support oocyte reawakening. We anticipate that application of Wnt inhibitors or activators in vitro will lead to improved fertility treatments.

  PublisherOA PDFDOI

• Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo

  Cell stem cell · 2020 · 152 citations

  • Biology
  • Cell biology
  • Computational biology
  PublisherOA PDFDOI

• β-catenin-mediated Wnt signal transduction proceeds through an endocytosis-independent mechanism

  Molecular Biology of the Cell · 2020-06-12 · 25 citations

  articleOpen accessSenior author

  The Wnt pathway is a key intercellular signaling cascade that regulates development, tissue homeostasis, and regeneration. However, gaps remain in our understanding of the molecular events that take place between ligand-receptor binding and target gene transcription. We used a novel tool for quantitative, real-time assessment of endogenous pathway activation, measured in single cells, to answer an unresolved question in the field-whether receptor endocytosis is required for Wnt signal transduction. We combined knockdown or knockout of essential components of clathrin-mediated endocytosis with quantitative assessment of Wnt signal transduction in mouse embryonic stem cells (mESCs). Disruption of clathrin-mediated endocytosis did not affect accumulation and nuclear translocation of β-catenin, as measured by single-cell live imaging of endogenous β-catenin, and subsequent target gene transcription. Disruption of another receptor endocytosis pathway, caveolin-mediated endocytosis, did not affect Wnt pathway activation in mESCs. Additional results in multiple cell lines support that endocytosis is not a requirement for Wnt signal transduction. We show that off-target effects of a drug used to inhibit endocytosis may be one source of the discrepancy among reports on the role of endocytosis in Wnt signaling.

  PublisherOA PDFDOI

• Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-05-25 · 2 citations

  preprintOpen access

  ABSTRACT In response to physiological demand, the pituitary gland generates new hormone-secreting cells from committed progenitor cells throughout life. It remains unclear to what extent pituitary stem cells (PSCs), which uniquely express SOX2, contribute to pituitary growth and renewal. Moreover, neither the signals that drive proliferation nor their sources have been elucidated. We have used genetic approaches in the mouse, showing that the WNT pathway is essential for proliferation of all lineages in the gland. We reveal that SOX2 + stem cells are a key source of WNT ligands. By blocking secretion of WNTs from SOX2 + PSCs in vivo , we demonstrate that proliferation of neighbouring committed progenitor cells declines, demonstrating that progenitor multiplication depends on the paracrine WNT secretion from SOX2 + PSCs. Our results indicate that stem cells can hold additional roles in tissue expansion and homeostasis, acting as paracrine signalling centres to coordinate the proliferation of neighbouring cells.

  PublisherOA PDFDOI

• A ZNRF3-dependent Wnt/β-catenin signaling gradient is required for adrenal homeostasis

  Genes & Development · 2019-01-28 · 109 citations

  articleOpen access

  Spatiotemporal control of Wnt signaling is essential for the development and homeostasis of many tissues. The transmembrane E3 ubiquitin ligases ZNRF3 (zinc and ring finger 3) and RNF43 (ring finger protein 43) antagonize Wnt signaling by promoting degradation of frizzled receptors. ZNRF3 and RNF43 are frequently inactivated in human cancer, but the molecular and therapeutic implications remain unclear. Here, we demonstrate that adrenocortical-specific loss of ZNRF3, but not RNF43, results in adrenal hyperplasia that depends on Porcupine-mediated Wnt ligand secretion. Furthermore, we discovered a Wnt/β-catenin signaling gradient in the adrenal cortex that is disrupted upon loss of ZNRF3. Unlike β-catenin gain-of-function models, which induce high Wnt/β-catenin activation and expansion of the peripheral cortex, ZNRF3 loss triggers activation of moderate-level Wnt/β-catenin signaling that drives proliferative expansion of only the histologically and functionally distinct inner cortex. Genetically reducing β-catenin dosage significantly reverses the ZNRF3-deficient phenotype. Thus, homeostatic maintenance of the adrenal cortex is dependent on varying levels of Wnt/β-catenin activation, which is regulated by ZNRF3.

  PublisherOA PDFDOI

• Wnt/β-catenin signaling regulates ependymal cell development and adult homeostasis

  Proceedings of the National Academy of Sciences · 2018-06-11 · 58 citations

  articleOpen accessSenior authorCorresponding

  Significance Little is known about the cellular origin and the molecular signals that regulate spinal cord ependymal cells. In this report, we characterize Wnt-responsive progenitor cells throughout spinal cord development, showing that they are restricted to the dorsal midline and give rise to dorsal ependymal cells in a spatially restricted pattern. In the postnatal and adult spinal cord, ependymal cells continue to exhibit Wnt/β-catenin signaling activity, which promotes ependymal cell proliferation. This is demonstrated by the genetic elimination of β-catenin and inhibition of Wnt secretion in Wnt-activated ependymal cells in vivo, which result in impaired proliferation. Our results thus reveal the molecular signals underlying the formation and regulation of spinal cord ependymal cells.

  PublisherOA PDFDOI

Frequent coauthors

• Catriona Y. Logan

  Howard Hughes Medical Institute

  20 shared

• Xinhong Lim

  16 shared

• Si Hui Tan

  Institute of Molecular and Cell Biology

  14 shared

• Hinako M. Takase

  RIKEN Center for Biosystems Dynamics Research

  12 shared

• Patrice Mollard

  Université de Montpellier

  8 shared

• Yasmine Kemkem

  8 shared

• Ellen Youngsoo Rim

  University of Otago

  8 shared

• Stéphanie Rodriguez

  8 shared

Education

• Ph.D., Developmental Biology

  University of California, San Francisco

  1984

• B.S., Biology

  University of California, San Diego

  1979