About

Yasuhiko Kawakami, PhD, is a Professor of Genetics, Cell Biology, and Development at the University of Minnesota. His research focuses on understanding the mechanisms that regulate the development of cells and their organization into functional systems within the animal body. He studies the mechanisms of development and regeneration using cell culture and animal models, specifically mice and zebrafish. His work aims to elucidate how progenitor cells are generated, how they differentiate, and how they undergo morphogenesis during embryonic development. Additionally, he investigates how dormant genetic systems are regulated for tissue regeneration and maintenance in adult animals. Kawakami's research includes studying the regeneration of fin and heart tissues in zebrafish, as well as understanding congenital limb malformations in humans, which result from patterning and proliferation issues of limb bud progenitor cells during embryonic development. His contributions contribute to the broader understanding of stem cell biology, tissue regeneration, and developmental processes.

Research topics

• Internal medicine
• Medicine
• Biology
• Endocrinology
• Pediatrics
• Genetics
• Oncology
• Bioinformatics
• Immunology

Selected publications

• Genetic knockout suggests Isl1 enhancer redundancy in mouse hindlimb development

  Developmental Biology · 2025-09-17

  articleSenior authorCorresponding
  PublisherDOI

• Visualization and Optical Manipulation of the Erectile Tissue, Penile Corpus Cavernous

  Biological and Pharmaceutical Bulletin · 2025-11-30

  articleOpen access

  Erectile responses in reproduction have not been analyzed extensively because of the limitation of their visualization analyses of inner penile structure and its dynamic changes. In addition, the complex and rapid changes of erectile responses require new manipulation techniques suitable to regulate erected and flaccid status. The current review describes novel strategies for the above visualization of erection and regulation of the erectile responses.

  PublisherOA PDFDOI

• Topohistological alignments of ocular/penile organs

  Anatomical Science International · 2025-05-13 · 1 citations

  reviewOpen access

  Mammalian visual and genital (hereafter mainly penile) organs have been extensively studied albeit separately. Both organ systems contain sensation devices necessary for visual perception and sexual intercourse. Their terminal structures are covered with eyelid/prepuce followed by the sensitive epithelia of cornea/glans facing the eyeball and glans. These structures have been closely studied in humans for appropriate visual perception and copulation and have thus been treated by numerous surgeries for long periods. Despite the vastly divergent anatomy and physiological functions, there are a few intriguing topohistological similarities for both structures, functions, and pathology. The current article focuses on such features from various viewpoints.

  PublisherOA PDFDOI

• Synergistic RAS-MAPK and AKT Activation in MYC-Driven Tumors via Adjacent PVT1 Rearrangements

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-22 · 1 citations

  preprintOpen access

  ABSTRACT MYC-driven (MYC+) cancers are aggressive and often fatal. MYC dysregulation is a key event in these cancers, but overexpression of MYC alone is not always enough to cause cancer. Plasmocytoma Variant Translocation 1 ( PVT1 ), a long non-coding RNA (lncRNA) adjacent to MYC on chromosome 8 is a rearrangement hotspot in many MYC+ cancers. In addition to being co-amplified with MYC, the genomic rearrangement at PVT1 involves translocation, which has had obscure functional consequences. We report that translocation at the PVT1 locus cause asymmetric enrichment of 5’-PVT1 and loss of 3’-PVT1. Despite being classified as a non-coding RNA, the retained 5’ region of PVT1 generates a circular RNA (CircPVT1) that codes for the novel peptide we call Firefox (FFX). FFX augments AKT signaling and synergistically activates MYC and mTORC1 in these cells. Further, the 3’ end of PVT1, which is lost during the translocation, codes for a tumor-suppressing micropeptide we named as Honeybadger (HNB). We demonstrate that HNB interacts with KRAS and disrupts the activation of KRAS effectors. Loss of HNB leads to activation of RAS/MAPK signaling pathway, and enhances MYC stability by promoting phosphorylation of MYC at Ser 62 . These findings identify PVT1 as a critical node that synchronizes MYC, AKT, and RAS-MAPK activities in cancer. Our study thus identifies a key mechanism by which rearrangements at the PVT1 locus activate additional oncogenic pathways that synergize with MYC to exacerbate the aggressiveness of MYC+ cancers. This newfound understanding explains the poor prognosis associated with MYC+ cancers and offers potential therapeutic targets that could be leveraged in treatment strategies for these cancers.

  PublisherOA PDFDOI

• METTL14 regulates chondrogenesis through the GDF5–RUNX–extracellular matrix gene axis during limb development

  Nature Communications · 2025-04-30 · 5 citations

  articleOpen access

  m6A RNA methylation is essential for many aspects of mammalian development but its roles in chondrogenesis remain largely unknown. Here, we show that m6A is necessary for chondrogenesis and limb morphogenesis using limb progenitor-specific knockout mice of Mettl14, an essential subunit in the m6A methyltransferase complex. The knockout disrupts cartilage anlagen formation in limb buds with 11 downregulated proteins known to dysregulate chondrogenesis and shorten limb skeletons upon mutation in mice and humans. Further studies show a gene regulatory hierarchy among the 11 proteins. m6A stabilizes the transcript and increases the protein level of GDF5, a BMP family member. This activates the chondrogenic transcription factor genes Runx2 and Runx3, whose mRNAs are also stabilized by m6A. They promote the transcription of six collagen genes and two other chondrogenic genes, Ddrgk1 and Pbxip1. Thus, this study uncovers an m6A-based cascade essential for chondrogenesis during limb skeletal development. Recent work shows that m6A RNA methylation is an important regulatory mechanism during development. Here they show that the m6A RNA methylase subunit METTL14 plays a critical role in chondrogenesis during mouse limb development, where it stabilizes Gdf5 and Runx2/3 mRNAs.

  PublisherOA PDFDOI

• Zebrafish sall1a and sall4 contribute to body elongation

  Developmental Biology · 2025-06-05

  articleSenior authorCorresponding
  PublisherDOI

• Genetic models of Cushing’s disease

  Pituitary · 2025-04-01

  review
  PublisherDOI

• Cis‐regulatory control of mammalian <i>Trps1</i> gene expression

  Journal of Experimental Zoology Part B Molecular and Developmental Evolution · 2024-02-18 · 2 citations

  articleOpen access

  TRPS1 serves as the causative gene for tricho-rhino phalangeal syndrome, known for its craniofacial and skeletal abnormalities. The Trps1 gene encodes a protein that represses Wnt signaling through strong interactions with Wnt signaling inhibitors. The identification of genomic cis-acting regulatory sequences governing Trps1 expression is crucial for understanding its role in embryogenesis. Nevertheless, to date, no investigations have been conducted concerning these aspects of Trps1. To identify deeply conserved noncoding elements (CNEs) within the Trps1 locus, we employed a comparative genomics approach, utilizing slowly evolving fish such as coelacanth and spotted gar. These analyses resulted in the identification of eight CNEs in the intronic region of the Trps1 gene. Functional characterization of these CNEs in zebrafish revealed their regulatory potential in various tissues, including pectoral fins, heart, and pharyngeal arches. RNA in-situ hybridization experiments revealed concordance between the reporter expression pattern induced by the identified set of CNEs and the spatial expression pattern of the trps1 gene in zebrafish. Comparative in vivo data from zebrafish and mice for CNE7/hs919 revealed conserved functions of these enhancers. Each of these eight CNEs was further investigated in cell line-based reporter assays, revealing their repressive potential. Taken together, in vivo and in vitro assays suggest a context-dependent dual functionality for the identified set of Trps1-associated CNE enhancers. This functionally characterized set of CNE-enhancers will contribute to a more comprehensive understanding of the developmental roles of Trps1 and can aid in the identification of noncoding DNA variants associated with human diseases.

  PublisherOA PDFDOI

• 8524 Pituitary Hormone Dysregulation In Symptomatic Long COVID: A Multi-Center Observational Study

  Journal of the Endocrine Society · 2024-10-01 · 1 citations

  articleOpen access

  Abstract Disclosure: S.L. Sims: None. A. Labadzhyan: None. Z. Chen: None. S. Kim: None. J. Brathwaite: None. L. Cullen: None. M. Koga: None. U. Cheliadinova: None. V. Hwe: None. D. Gomez: None. C. Andriakos: None. T. Melnik: None. E. Puig-Wong: None. S. Whelan: None. S. Cheng: None. S. Joung: None. Z. Abelev: None. C. Le: None. R. Zabner: None. Y. Kawakami: None. T. Araki: Consulting Fee; Self; Chiesi. Objective: Pituitary hormone dysregulation has been reported in symptomatic long COVID, but it has not been rigorously studied. We conducted a multicenter observational cross-sectional study to assess pituitary hormone levels in long COVID patients and a longitudinal study to follow patients with abnormal results. Methods: Male and female adults with confirmed symptomatic long COVID were recruited from post COVID clinics at Mount Sinai in New York, Cedars-Sinai in Los Angeles, and the University of Minnesota, as well as nationwide physician referrals. Pituitary hormone levels were measured, and because fatigue is common in long COVID, patients completed the QoL-AGHDA survey. Those who exceeded pre-determined survey cutoffs or demonstrated any hormone abnormality were invited to the longitudinal study to repeat surveys and blood work every 3 months. A separate cohort with banked serum samples from before and 3, 6, and 9 months after subacute COVID was used as a comparator. Correlation analysis examined associations between QoL-AGHDA scores and pituitary hormone levels. Results: 246 patients were enrolled in the cross-sectional study after a median of 17.0 months (range, 1-39) since the most recent SARS-CoV2 infection prior to the onset of long COVID symptoms. 56% were enrolled in the longitudinal study due to a high questionnaire score and/or pituitary hormone abnormalities. Current mean follow-up period is 7.95 ± 3.2 months. Mildly elevated prolactin levels were most frequent, observed in 12.7% of patients (males 14.0%, females 12.2%). These patients presented post-COVID with galactorrhea, irregular menses, erectile dysfunction, and nonspecific symptoms of hyperprolactinemia. On follow-up, mild hyperprolactinemia tended to persist. Mildly low IGF1 levels (Z-score &amp;lt;-1.0) were observed in 9.0% of patients (males 6.3%, females 10.0%); on follow-up, IGF1 levels recovered in only 15% of these patients. 2.0% of the entire cohort showed transiently elevated IGF1 levels (Z-score &amp;gt;2.0). Low morning cortisol (&amp;lt;5.0 µg/dL) was observed in 3.3% of patients, but response to cosyntropin stimulation was normal. Mild secondary hypothyroidism was observed in 3.7% of all patients, and mild hypogonadism was observed in 7.8% of males. There was no correlation between QoL-AGHDA score and level of each pituitary hormone. After excluding pre-COVID hormone abnormalities in the post subacute COVID cohort, the rate of hyperprolactinemia was lower than that seen in the long COVID cohort (1% vs 12.7%). The rate of low IGF1 levels was higher in the subacute COVID cohort (22% vs 9.0), but unlike with long COVID, low IGF1 levels after subacute COVID recovered in 3-6 months. Conclusion: Abnormalities in pituitary hormone levels in symptomatic long COVID are frequent, with persistent hyperprolactinemia in &amp;gt;10%. Pituitary hormone screening may be important in patients with prolonged symptomatic long COVID. Presentation: 6/3/2024

  PublisherOA PDFDOI

• <i>Sall</i> genes regulate hindlimb initiation in mouse embryos

  Genetics · 2024-02-22 · 4 citations

  articleOpen accessSenior authorCorresponding

  Vertebrate limbs start to develop as paired protrusions from the lateral plate mesoderm at specific locations of the body with forelimb buds developing anteriorly and hindlimb buds posteriorly. During the initiation process, limb progenitor cells maintain active proliferation to form protrusions and start to express Fgf10, which triggers molecular processes for outgrowth and patterning. Although both processes occur in both types of limbs, forelimbs (Tbx5), and hindlimbs (Isl1) utilize distinct transcriptional systems to trigger their development. Here, we report that Sall1 and Sall4, zinc finger transcription factor genes, regulate hindlimb initiation in mouse embryos. Compared to the 100% frequency loss of hindlimb buds in TCre; Isl1 conditional knockouts, Hoxb6Cre; Isl1 conditional knockout causes a hypomorphic phenotype with only approximately 5% of mutants lacking the hindlimb. Our previous study of SALL4 ChIP-seq showed SALL4 enrichment in an Isl1 enhancer, suggesting that SALL4 acts upstream of Isl1. Removing 1 allele of Sall4 from the hypomorphic Hoxb6Cre; Isl1 mutant background caused loss of hindlimbs, but removing both alleles caused an even higher frequency of loss of hindlimbs, suggesting a genetic interaction between Sall4 and Isl1. Furthermore, TCre-mediated conditional double knockouts of Sall1 and Sall4 displayed a loss of expression of hindlimb progenitor markers (Isl1, Pitx1, Tbx4) and failed to develop hindlimbs, demonstrating functional redundancy between Sall1 and Sall4. Our data provides genetic evidence that Sall1 and Sall4 act as master regulators of hindlimb initiation.

  PublisherOA PDFDOI

Recent grants

• Genetic regulation of progenitor cells in appendicular skeletal development

  NIH · $3.3M · 2013–2024

• Limb-Type Specific Distinct Upstream Regulation of a Common Hand2-Shh Pathway

  NIH · $366k · 2012–2015

• Mechanisms for post-COVID pituitary damage

  NIH · $1.2M · 2021–2025

Frequent coauthors

• Juan Carlos Izpisúa Belmonte

  Altos Labs

  93 shared

• Hiroko Kawakami

  University of Minnesota

  54 shared

• Ángel Raya

  Duran i Reynals Hospital

  48 shared

• Kenneth R. Chien

  Karolinska Institutet

  30 shared

• Jianming Wang

  Wellcome Trust

  30 shared

• Pilar Ruiz‐Lozano

  Imperial College London

  30 shared

• Tsutomu Nohno

  Okayama University

  27 shared

• Perla Kaliman

  Universitat Oberta de Catalunya

  25 shared

Education

• Ph.D.

  Okayama University

  1996

Awards & honors

• Dr. James E. Rubin Medical Memorial Award
• Veneziale-Steer Award
• Dr. Marvin and Hadassah Bacaner Research Awards
• Schmidt Steer Award
• Steer Pruitt Award