Commentary - Journal of Clinical Cardiology (2020) Volume 1, Issue 1
A View on the Contribution of Hedgehog Signalling to Ventricular Septal Development
Institute for Animal Developmental and Molecular Biology, Heinrich Heine University, 40225 Düsseldorf, Germany
- *Corresponding Author:
- Christoph Gerhardt
Received date: June 10, 2020; Accepted date: August 26, 2020
Citation: Gerhardt C. A View on the Contribution of Hedgehog Signalling to Ventricular Septal Development. J Clin Cardiol.
Copyright: © 2020 Gerhardt C. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The ventricular septal defect (VSD) is the most frequent congenital heart disease in humans. It is defined as an opening in the septum separating the left and the right ventricle. This gap results in a mixture of oxygenated and deoxygenated blood and in an enhanced blood flow towards the lung and the left ventricle , a condition that leads to severe diseases such as left ventricular hypertrophy as well as pulmonary edema and dilatation [2,3]. The molecular mechanisms underlying the development of VSDs are poorly understood. The recently published review article entitled “The Role of Hedgehog Signalling in the Formation of the Ventricular Septum” discusses the importance of the Hedgehog (HH) signalling pathway in the formation of the ventricular septum (VS) . HH signalling begins with the binding of the HH protein to its receptor Patched (PTC1) which localises in the membrane of primary cilia, little cellular protrusions dedicated to signal mediation. Low-density lipoprotein receptor related protein 2 (LRP2) participates in this binding event . The HH/PTC1 complex leaves the cilium and, in turn, Smoothened (SMO) enters the ciliary membrane. Subsequently, SMO releases the full-length Glioblastoma 2 (GLI2) and Glioblastoma 3 (GLI3) proteins from a complex with Suppressor of Fused (SUFU) and converts them into transcriptional activators (GLI2-A and GLI3-A) [6,7]. Proteins such as Broad-Minded (BROMI), Ellis Van Creveld 1 (EVC1) and Ellis Van Creveld 2 (EVC2) are involved in the activation of GLI2 and GLI3 [8-14]. GLI2-A and GLI3-A enter the nucleus and induce the expression of HH target genes. The Intraflagellar transport proteins 25 and 27 (IFT25 and IFT27) ensure the transport of several HH signaling components and the deficiency of IFT25 or IFT27 results in reduced HH target gene expression [15-17]. Without the HH ligand, PTC1 remains in the ciliary membrane and blocks the ciliary entry of SMO. In the absence of SMO, the full-length GLI2 and GLI3 proteins are proteolytically processed into transcriptional repressors (GLI2-R and GLI3-R) by the cilia-regulated proteasome [18-20].
Further proteins such as Protein kinase A (PKA), Casein
kinase 1 (CK1), Glycogen synthase kinase 3-β (GSK3-β),
Kinesin family member 7 (KIF7) and Fuzzy (FUZ) are
required for GLI2 and GLI3 processing [21-26].
The fact that HH signalling mouse mutants such as Shh, Lrp2, Sufu, Bromi, Ift25, Ift27, Gsk3-β, Kif7 and Fuz mutant mice display defects in VS outgrowth implies an essential role of HH signalling in VS development [15,16,27-30]. Furthermore, mutations of EVC1 and EVC2 cause VSDs in humans [31-33]. Since mutations in genes whose products positively regulate HH signalling and mutations in genes which encode proteins negatively controlling HH signalling lead to the occurrence of VSDs, our review article rises the question which role HH signalling plays in the development of the VS and of VSDs.
As outlined above, GLI3 is able to act as a transcriptional activator and induce HH target gene expression or as a transcriptional repressor and inhibit HH target gene expression. Previously, we demonstrated that the absence of the ciliary protein Retinitis pigmentosa GTPase Regulator Interacting Protein 1 Like (RPGRIP1L) leads to a disturbed GLI3 processing and also to the development of VSDs [19,34] suggesting that the inhibition of HH signalling might be important to ensure proper VS formation. Remarkably, loss of GLI3 does not affect VS development . In our very recent preprint , we provide further insight into this topic by analysing mouse embryos which produce GLI3-R but lack GLI3-A (Gli3Δ699/ Δ699 embryos) [37,38]. Importantly, these embryos display reduced HH signalling and VSDs proposing that proper HH signalling is essential for the development of the VS. The finding of VSDs in Rpgrip1l-/- mouse embryos might also be traced back to a potential role of RPGRIP1L in the transformation of GLI3 into GLI3-A . Taking up
a question from our review article, namely whether it is
possible to prevent the development of VSDs by targeting
HH signalling in pregnancy, our new results suggest
that the activation of HH signalling (e.g. by using small
molecules) could avoid the occurrence of VSDs.
- LD BM, Lange RA. Congenital heart disease inadults.
First of two parts. The New England Journal of Medicine.
- Ferreira AJ, Shenoy V, Yamazato Y, Sriramula S, Francis
J, Yuan L, et al. Evidence for angiotensin-converting
enzyme 2 as a therapeutic target for the prevention of
pulmonary hypertension. American Journal of Respiratory
and Critical Care Medicine. 2009 Jun 1;179(11):1048-54.
- Selicorni A, Colli AM, Passarini A, Milani D, Cereda
A, Cerutti M, et al. Analysis of congenital heart defects
in 87 consecutive patients with Brachmann-de Lange
syndrome. American Journal of Medical Genetics Part A.
- Wiegering A, Rüther U, Gerhardt C. The role of Hedgehog
signalling in the formation of the ventricular septum.
Journal of Developmental Biology. 2017 Dec;5(4):17.
- Christ A, Christa A, Kur E, Lioubinski O, Bachmann
S, Willnow TE, et al. LRP2 is an auxiliary SHH receptor
required to condition the forebrain ventral midline
for inductive signals. Developmental Cell. 2012 Feb
- Chen MH, Wilson CW, Li YJ, Law KK, Lu CS,
Gacayan R, Zhang X, Hui CC, Chuang PT. Ciliumindependent
regulation of Gli protein function by Sufu in
Hedgehog signaling is evolutionarily conserved. Genes &
Development. 2009 Aug 15;23(16):1910-28.
- Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi
R. The output of Hedgehog signaling is controlled by the
dynamic association between Suppressor of Fused and the
Gli proteins. Genes & Development. 2010 Apr 1;24(7):670-
- Ruiz-Perez VL, Blair HJ, Rodriguez-Andres ME,
Blanco MJ, Wilson A, Liu YN, et al. Evc is a positive
mediator of Ihh-regulated bone growth that localises at
the base of chondrocyte cilia. Development. 2007 Aug
- Valencia M, Lapunzina P, Lim D, Zannolli R, Bartholdi
D, Wollnik B, et al. Widening the mutation spectrum of
EVC and EVC2: ectopic expression of Weyer variants in
NIH 3T3 fibroblasts disrupts Hedgehog signaling. Human
Mutation. 2009 Dec;30(12):1667-75.
- Blair HJ, Tompson S, Liu YN, Campbell J, MacArthur
K, Ponting CP, et al. Evc2 is a positive modulator of
Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus. BMC Biology.
2011 Dec 1;9(1):14.
- Dorn KV, Hughes CE, Rohatgi R. A Smoothened-Evc2
complex transduces the Hedgehog signal at primary cilia.
Developmental Cell. 2012 Oct 16;23(4):823-35.
- Yang C, Chen W, Chen Y, Jiang J. Smoothened
transduces Hedgehog signal by forming a complex with
Evc/Evc2. Cell Research. 2012 Nov;22(11):1593-604.
- Caparrós-Martín JA, Valencia M, Reytor E, Pacheco
M, Fernandez M, Perez-Aytes A, et al. The ciliary Evc/
Evc2 complex interacts with Smo and controls Hedgehog
pathway activity in chondrocytes by regulating Sufu/Gli3
dissociation and Gli3 trafficking in primary cilia. Human
Molecular Genetics. 2013 Jan 1;22(1):124-39.
- Ko HW, Norman RX, Tran J, Fuller KP, Fukuda M,
Eggenschwiler JT. Broad-minded links cell cycle-related
kinase to cilia assembly and hedgehog signal transduction.
Developmental Cell. 2010 Feb 16;18(2):237-47.
- Keady BT, Samtani R, Tobita K, Tsuchya M, San Agustin
JT, Follit JA, et al. IFT25 links the signal-dependent
movement of Hedgehog components to intraflagellar
transport. Developmental Cell. 2012 May 15;22(5):940-51.
- Eguether T, San Agustin JT, Keady BT, Jonassen JA,
Liang Y, Francis R, et al. IFT27 links the BBSome to IFT
for maintenance of the ciliary signaling compartment.
Developmental Cell. 2014 Nov 10;31(3):279-90.
- Yang N, Li L, Eguether T, Sundberg JP, Pazour
GJ, Chen J. Intraflagellar transport 27 is essential for
hedgehog signaling but dispensable for ciliogenesis during
hair follicle morphogenesis. Development. 2015 Jun
- Wang B, Fallon JF, Beachy PA. Hedgehog-regulated
processing of Gli3 produces an anterior/posterior
repressor gradient in the developing vertebrate limb. Cell.
2000 Feb 18;100(4):423-34.
- Gerhardt C, Lier JM, Burmühl S, Struchtrup A,
Deutschmann K, Vetter M, Leu T, Reeg S, Grune T,
Rüther U. The transition zone protein Rpgrip1l regulates
proteasomal activity at the primary cilium. Journal of Cell
Biology. 2015 Jul 6;210(1):1027-45.
- Gerhardt C, Wiegering A, Leu T, Rüther U. Control
of Hedgehog signalling by the cilia-regulated proteasome.
Journal of Developmental Biology. 2016 Sep;4(3):27.
- Tuson M, He M, Anderson KV. Protein kinase A acts
at the basal body of the primary cilium to prevent Gli2
activation and ventralization of the mouse neural tube.
Development. 2011 Nov 15;138(22):4921-30.
- Wang B, Li Y. Evidence for the direct involvement
of ßTrCP in Gli3 protein processing. Proceedings of the
National Academy of Sciences. 2006 Jan 3;103(1):33-8.
- Pan Y, Bai CB, Joyner AL, Wang B. Sonic hedgehog
signaling regulates Gli2 transcriptional activity by
suppressing its processing and degradation. Molecular
and Cellular Biology. 2006 May 1;26(9):3365-77.
- Cheung HO, Zhang X, Ribeiro A, Mo R, Makino S,
Puviindran V, et al. The kinesin protein Kif7 is a critical
regulator of Gli transcription factors in mammalian
hedgehog signaling. Science Signaling. 2009 Jun
- Endoh-Yamagami S, Evangelista M, Wilson D, Wen
X, Theunissen JW, Phamluong K, Davis M, Scales SJ,
Solloway MJ, de Sauvage FJ, Peterson AS. The mammalian
Cos2 homolog Kif7 plays an essential role in modulating
Hh signal transduction during development. Current
biology. 2009 Aug 11;19(15):1320-6.
- Heydeck W, Zeng H, Liu A. Planar cell polarity effector
gene Fuzzy regulates cilia formation and Hedgehog signal
transduction in mouse. Developmental Dynamics. 2009
- Smoak IW, Byrd NA, Abu-Issa R, Goddeeris MM,
Anderson R, Morris J, et al. Sonic hedgehog is required
for cardiac outflow tract and neural crest cell development.
Developmental Biology. 2005 Jul 15;283(2):357-72.
- Li Y, Klena NT, Gabriel GC, Liu X, Kim AJ, Lemke
K, et al. Global genetic analysis in mice unveils central
role for cilia in congenital heart disease. Nature. 2015
- Kerkela R, Kockeritz L, MacAulay K, Zhou J, Doble
BW, Beahm C, et al. Deletion of GSK-3ß in mice leads to
hypertrophic cardiomyopathy secondary to cardiomyoblast
hyperproliferation. The Journal of Clinical Investigation.
2008 Nov 3;118(11):3609-18.
- Coles GL, Ackerman KG. Kif7 is required for the
patterning and differentiation of the diaphragm in a
model of syndromic congenital diaphragmatic hernia.
Proceedings of the National Academy of Sciences. 2013
- Digilio MC, Marino B, Ammirati A, Borzaga U,
Giannotti A, Dallapiccola B. Cardiac malformations in
patients with oral-facial-skeletal syndromes: Clinical
similarities with heterotaxia. American Journal of Medical
Genetics. 1999 Jun 4;84(4):350-6.
- Sund KL, Roelker S, Ramachandran V, Durbin L,
Benson DW. Analysis of Ellis van Creveld syndrome gene
products: implications for cardiovascular development
and disease. Human Molecular Genetics. 2009 May
- Liu F, Liu X, Xu Z, Yuan P, Zhou Q, Jin J, et al.
Molecular mechanisms of Ellis-van Creveld gene variations
in ventricular septal defect. Molecular Medicine Reports.
2018 Jan 1;17(1):1527-36.
- Gerhardt C, Lier JM, Kuschel S, Rüther U. The ciliary
protein Ftm is required for ventricular wall and septal
development. PLoS One. 2013 Feb 28;8(2):e57545.
- Johnson DR. Extra-toes: a new mutant gene causing
multiple abnormalities in the mouse. Development. 1967
- Wiegering A, Adibi P, Rüther U, Gerhardt C. Gain-offunction
mutation in Gli3 causes ventricular septal defects.
bioRxiv. 2020 Jan 1.
- Bo¨se J, Grotewold L, Ru¨ther U. Pallister–Hall
syndrome phenotype in mice mutant for Gli3. Human
molecular genetics. 2002 May 1;11(9):1129-35.
- Hill P, Wang B, Rüther U. The molecular basis of
Pallister–Hall associated polydactyly. Human Molecular
Genetics. 2007 Sep 1;16(17):2089-96.