Abstract
A fundamental process in biology is the de novo formation and morphogenesis of polarized tubules. Although these processes are essential for the formation of multiple metazoan organ systems, little is known about the molecular mechanisms that regulate them. In this study, we have characterized several steps in tubule formation and morphogenesis using the mouse kidney as a model system. We report that kidney mesenchymal cells contain discrete Par3-expressing membrane microdomains that become restricted to an apical domain, coinciding with lumen formation. Once lumen formation has been initiated, elongation occurs by simultaneous extension and additional de novo lumen generation. We demonstrate that lumen formation and elongation require afadin, a nectin adaptor protein implicated in adherens junction formation. Mice that lack afadin in nephron precursors show evidence of Par3-expressing membrane microdomains, but fail to develop normal apical-basal polarity and generate a continuous lumen. Absence of afadin led to delayed and diminished integration of nectin complexes and failure to recruit R-cadherin. Furthermore, we demonstrate that afadin is required for Par complex formation. Together, these results suggest that afadin acts upstream of the Par complex to regulate the integration and/or coalescence of membrane microdomains, thereby establishing apical-basal polarity and lumen formation/elongation during kidney tubulogenesis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1774-1784 |
| Number of pages | 11 |
| Journal | Development (Cambridge) |
| Volume | 140 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 2013 |
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Keywords
- Afadin (Mllt4)
- Cadherin
- Kidney development
- Lumen
- Nectin
- Par complex
- Polarity
- Tubulogenesis
ASJC Scopus subject areas
- Developmental Biology
- Molecular Biology
Cite this
De novo lumen formation and elongation in the developing nephron : A central role for afadin in apical polarity. / Yang, Zhufeng; Zimmerman, Susan; Brakeman, Paul R.; Beaudoin, Gerard M.; Reichardt, Louis F.; Marciano, Denise K.
In: Development (Cambridge), Vol. 140, No. 8, 04.2013, p. 1774-1784.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - De novo lumen formation and elongation in the developing nephron
T2 - A central role for afadin in apical polarity
AU - Yang, Zhufeng
AU - Zimmerman, Susan
AU - Brakeman, Paul R.
AU - Beaudoin, Gerard M.
AU - Reichardt, Louis F.
AU - Marciano, Denise K.
PY - 2013/4
Y1 - 2013/4
N2 - A fundamental process in biology is the de novo formation and morphogenesis of polarized tubules. Although these processes are essential for the formation of multiple metazoan organ systems, little is known about the molecular mechanisms that regulate them. In this study, we have characterized several steps in tubule formation and morphogenesis using the mouse kidney as a model system. We report that kidney mesenchymal cells contain discrete Par3-expressing membrane microdomains that become restricted to an apical domain, coinciding with lumen formation. Once lumen formation has been initiated, elongation occurs by simultaneous extension and additional de novo lumen generation. We demonstrate that lumen formation and elongation require afadin, a nectin adaptor protein implicated in adherens junction formation. Mice that lack afadin in nephron precursors show evidence of Par3-expressing membrane microdomains, but fail to develop normal apical-basal polarity and generate a continuous lumen. Absence of afadin led to delayed and diminished integration of nectin complexes and failure to recruit R-cadherin. Furthermore, we demonstrate that afadin is required for Par complex formation. Together, these results suggest that afadin acts upstream of the Par complex to regulate the integration and/or coalescence of membrane microdomains, thereby establishing apical-basal polarity and lumen formation/elongation during kidney tubulogenesis.
AB - A fundamental process in biology is the de novo formation and morphogenesis of polarized tubules. Although these processes are essential for the formation of multiple metazoan organ systems, little is known about the molecular mechanisms that regulate them. In this study, we have characterized several steps in tubule formation and morphogenesis using the mouse kidney as a model system. We report that kidney mesenchymal cells contain discrete Par3-expressing membrane microdomains that become restricted to an apical domain, coinciding with lumen formation. Once lumen formation has been initiated, elongation occurs by simultaneous extension and additional de novo lumen generation. We demonstrate that lumen formation and elongation require afadin, a nectin adaptor protein implicated in adherens junction formation. Mice that lack afadin in nephron precursors show evidence of Par3-expressing membrane microdomains, but fail to develop normal apical-basal polarity and generate a continuous lumen. Absence of afadin led to delayed and diminished integration of nectin complexes and failure to recruit R-cadherin. Furthermore, we demonstrate that afadin is required for Par complex formation. Together, these results suggest that afadin acts upstream of the Par complex to regulate the integration and/or coalescence of membrane microdomains, thereby establishing apical-basal polarity and lumen formation/elongation during kidney tubulogenesis.
KW - Afadin (Mllt4)
KW - Cadherin
KW - Kidney development
KW - Lumen
KW - Nectin
KW - Par complex
KW - Polarity
KW - Tubulogenesis
UR - http://www.scopus.com/inward/record.url?scp=84875466076&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875466076&partnerID=8YFLogxK
U2 - 10.1242/dev.087957
DO - 10.1242/dev.087957
M3 - Article
C2 - 23487309
AN - SCOPUS:84875466076
VL - 140
SP - 1774
EP - 1784
JO - Development (Cambridge)
JF - Development (Cambridge)
SN - 0950-1991
IS - 8
ER -