Cardiomyocyte orientation modulated by the Numb family proteins-N-cadherin axis is essential for ventricular wall morphogenesis

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • Albany Medical College
  • Fudan University
  • Nanchang University
  • Yale University
  • Tianjin University of Science & Technology

Details

Original languageEnglish (US)
Pages (from-to)15560-15569
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number31
StatusPublished - Jul 30 2019
Peer-reviewedYes

Abstract

The roles of cellular orientation during trabecular and ventricular wall morphogenesis are unknown and so are the underlying mechanisms that regulate cellular orientation. Myocardial-specific Numb and Numblike double-knockout (MDKO) hearts display a variety of defects including in cellular orientation patterns of mitotic spindle orientation trabeculation and ventricular compaction. Furthermore Numb- and Numblike-null cardiomyocytes exhibit cellular behaviors distinct from those of control cells during trabecular morphogenesis based on single-cell lineage tracing. We investigated how Numb regulates cellular orientation and behaviors and determined that N-cadherin levels and membrane localization are reduced in MDKO hearts. To determine how Numb regulates N-cadherin membrane localization we generated an mCherry:Numb knockin line and found that Numb localized to diverse endocytic organelles but mainly to the recycling endosome. Consistent with this localization cardiomyocytes in MDKO did not display defects in N-cadherin internalization but rather in postendocytic recycling to the plasma membrane. Furthermore N-cadherin overexpression via a mosaic model partially rescued the defects in cellular orientation and trabeculation of MDKO hearts. Our study unravels a phenomenon that cardiomyocytes display spatiotemporal cellular orientation during ventricular wall morphogenesis and its disruption leads to abnormal trabecular and ventricular wall morphogenesis. Furthermore we established a mechanism by which Numb modulates cellular orientation and consequently trabecular and ventricular wall morphogenesis by regulating N-cadherin recycling to the plasma membrane.

    Research areas

  • Cellular orientation, Endocytosis, Numb family proteins, Single-cell lineage tracing, Trabecular morphogenesis

Citation formats

APA

Miao, L., Li, J., Li, J., Lu, Y., Shieh, D., Mazurkiewicz, J. E., ... Wu, M. (2019). Cardiomyocyte orientation modulated by the Numb family proteins-N-cadherin axis is essential for ventricular wall morphogenesis. Proceedings of the National Academy of Sciences of the United States of America, 116(31), 15560-15569. https://doi.org/10.1073/pnas.1904684116

Harvard

Miao, L, Li, J, Li, J, Lu, Y, Shieh, D, Mazurkiewicz, JE, Barroso, M, Schwarz, JJ, Xin, HB, Singer, HA, Vincent, PA, Zhong, W, Radice, GL, Wan, LQ, Fan, ZC, Huang, G & Wu, M 2019, 'Cardiomyocyte orientation modulated by the Numb family proteins-N-cadherin axis is essential for ventricular wall morphogenesis', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 31, pp. 15560-15569. https://doi.org/10.1073/pnas.1904684116