ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2- and heregulin-deficient mice

Abstract

Heregulins bind directly to ErbB3 and ErbB4 receptors, leading to multiple dimerization possibilities including heterodimerization with the ErbB2 receptor. We have generated ErbB3-, ErbB2- and heregulin-deficient mice to assess their roles in development and differentiation. Heregulin(−/−) and ErbB2(−/−) embryos died on E10.5 due to a lack of cardiac ventricular myocyte differentiation; ErbB3(−/−) embryos survived until E13.5 exhibiting cardiac cushion abnormalities leading to blood reflux through defective valves. In ErbB3(−/−) embryos, the midbrain/hindbrain region was strikingly affected, with little differentiation of the cerebellar plate. Cranial ganglia defects, while present in all three nulls, were less severe in ErbB3(−/−) embryos. The cranial ganglia defects, along with a dramatic reduction in Schwann cells, enteric ganglia and adrenal chromaffin cells, suggests a generalized effect on the neural crest. Numerous organs, including the stomach and pancreas also exhibited anomalous development.

Behavioral profile of a heterozygous mutant mouse model for EGF-like domain neuregulin 1.

“…Genetic mouse model for Described in Behavioral phenotype of mutant mice EGF-like domain Nrg1 (heterozygous) Background: C57BL/6 (Michailov et al, 2004) -developed by (Meyer & Birchmeier, 1995) WT-like performance in bar test and rotarod EGF-like domain Nrg1 (heterozygous) Background: C57BL/6 ϫ 129/SVEV (Gerlai et al, 2000;Stefansson et al, 2002) developed by (Erickson et al, 1997) Hyperactivity in OF but no impaired habituation, WT-like SA, improved rotarod performance, 16% fewer functional NMDA receptors Transmembrane domain Nrg1 (heterozygous) Background: C57BL/6 (Boucher et al, 2007a(Boucher et al, , 2007bKarl et al, 2007;O'Tuathaigh C et al, 2007;O'Tuathaigh C et al, 2006;Stefansson et al, 2002) developed by (Stefansson et al, 2002) Clozapine-reversible hyperactivity in OF, impaired habituation to novelty, reduced anxiety, moderate PPI deficits, WT-like spatial memory and SA, impaired response to social novelty, increased aggression; elevated susceptibility to EE and the neurobehavioural effects of ⌬ 9 -THC -age-dependent and sexually dimorphic phenotype Immunoglobulin-like domain Nrg1…”

Source and Impact of the EGF Family of Ligands on Intestinal Stem Cells

“…There is likely to be some functional redundancy given triple knockout of three of the ligands EGF, AREG, and TGFα has little effect on the intestinal epithelium with animals being viable and fertile (Luetteke et al, 1999). Similarly, single knockout of the other EGF ligands does not affect embryonic development, with the exception of Nrg1, which results in aberrant heart and neural development leading to embryonic lethality (Meyer and Birchmeier, 1995;Erickson et al, 1997). Although knockout of EGF in mice produces little effect on the epithelium, the loss of NRG1 under homeostatic conditions produces a significant reduction in proliferative stem and progenitor cells (Jardé et al, 2020; Table 1).…”

“…Although knockout of EGF in mice produces little effect on the epithelium, the loss of NRG1 under homeostatic conditions produces a significant reduction in proliferative stem and progenitor cells (Jardé et al, 2020; Table 1). Loss of each individual ERBB receptor is lethal and produces severe defects with significant intestinal abnormalities observed (Gassmann et al, 1995;Lee et al, 1995;Miettinen et al, 1995;Threadgill et al, 1995;Erickson et al, 1997;Riethmacher et al, 1997). Genetic background has a considerable effect on the penetrance of phenotypes (see Table 1) with knockout of EGFR exhibiting variable phenotypes from peri-implantation lethality to viable animals with multi-organ defects (Sibilia and Wagner, 1995;Threadgill et al, 1995).…”

“…Erbb2 KO embryos die on E10.5 and display cardiac and neural malfunction. Erickson et al, 1997 Erbb2 (i) Mice harboring intestinal specific loss of Erbb2 are viable and display no obvious gut abnormalities. Zhang et al, 2012 However, ErbB2 is required for tissue regeneration following DSS mediated injury.…”

The Role of Epidermal Growth Factor Receptor Family of Receptor Tyrosine Kinases in Mediating Diabetes-Induced Cardiovascular Complications

“…Observations in engineered knockout (KO) or mutant mice of ErbB1, ErbB2, ErbB3, ErbB4 highlighted the lethal phenotypes and heart defects that can arise as a result of a deficiency in the number or signaling of these receptors (for review see also Sanchez-Soria and Camenisch, 2010). ErbB1 KO and mutant mice displayed semilunar valve defects (Sibilia and Wagner, 1995;Chen et al, 2000) whilst disrupted endocardial cushion/heart valve mesenchyme formation was noted in ErbB3 KO mice that ultimately leads to death of embryos within 2 weeks (Erickson et al, 1997;Camenisch et al, 2002). ErbB2 and ErbB4 KO mice lack ventricular trabeculation-a key process in the maturation of ventricles and necessary for physical contractility and normal blood flow (Gassmann et al, 1995;Lee et al, 1995;Chan et al, 2002;Negro et al, 2004).…”