Table 1.
Summary of MAPK and PI3K mutant phenotypes discussed in the text. For simplicity, growth factor receptor mutations have been omitted.
| Genotype | NC Defects | Lethality/Other Defects | Reference |
|---|---|---|---|
| ERK1/2 Pathway LoF | |||
| Mapk1−/− (Erk2) | NA | Peri-implantation lethal. Extraembryonic tissue defects. | (Hatano et al., 2003; Saba-El-Leil et al., 2003) |
| Mapk3−/− (Erk1) | NA | Viable and fertile. Background-dependent hyperactivity. | (Mazzucchelli et al., 2002; Pages et al., 1999) |
| Map2k1−/− (Mek1) | NA | Mid-gestation lethal. Placental defects. | (Giroux et al., 1999) |
| Map2k2−/− (Mek2) | NA | Viable and fertile. | (Belanger et al., 2003) |
| Mapk1flox/flox; Wnt1-Cre | Micrognathia, hypoplastic maxilla, cleft palate, DORV, PTA, VSD, osteoblast differentiation defects. | Perinatal lethal. | (Newbern et al., 2008; Parada et al., 2015) |
| Mapk1flox/flox; Mapk3−/−; Wnt1-Cre | Above + aglossia, missing external ear and thymus, misplaced thyroid. Hypoplastic PAs at E10.5. No NCC- derived Schwann cells. DRG degenerate. Lacrimal aplasia. | Lethal E18-E19. | (Garg et al., 2017; Newbern et al., 2008; 2011) |
| Mek1flox/flox; Mek2−/−; Wnt1-Cre | Similar to above. | Similar to above. | (Garg et al., 2017; Newbern et al., 2008; 2011) |
| Brafflox/flox; Raf1flox/flox; Wnt1-Cre | Similar craniofacial and cardiovascular phenotypes as above. | Similar to above. | (Newbern et al., 2008) |
| Mapk1flox/flox; Mapk3−/−; Dhh-Cre | PNS not analyzed. Hypo- and unmyelinated PNS axons. Tremor, hindlimb paresis. | Lethal by P28. | (Newbern et al., 2011) |
| Mapk1Δ/flox; Sox2-Cre | Agnathia, aglossia, hypoplastic maxilla, VSD, PSA. | Lethal by E16.5. Short forelimbs and missing hindlimbs. | (Frémin et al., 2015) |
| Mapk1Δ/flox; Mapk3+/−; Sox2-Cre | NA | Small size, lethal E10.5. | (Frémin et al., 2015) |
| Ptpn11flox/flox (Shp2); Wnt1-Cre | Reduced or absent NCC-derived craniofacial bones and cartilage, PTA, variable VSD. Osteoblast differentiation defects. Lacrimal aplasia. | Lethal between E15.5 and birth. | (Garg et al., 2017; Nakamura et al., 2009a) |
| ERK1/2 Pathway GoF | |||
| Tg(CAG-cat,- Ptpn11Q79R); Wnt1-Cre | Variable cleft lip/palate. Domed skull, hypertelorism, small size. Osteoblast differentiation defects. | Lethal P1–P5 if cleft lip/palate present. | (Nakamura et al., 2009b) |
| ROSA26-Map2k1DD; Dhh-Cre and ROSA26- Map2k1DD; Egr2-Cre | Continuous myelin growth in PNS Schwann cells. | NA | (Sheean et al., 2014) |
| Tg(P0-Raf1/ER); Activated in adult Schwann cells | Schwann cell dedifferentiation, increased proliferation, muscle weakening. | NA | (Napoli et al., 2012) |
| ERK1/2 Pathway Effectors | |||
| Rps6ka−/− (Rsk2) | Delayed mineralization of craniofacial bones. Wide cranial sutures at birth. Dental defects. | Viable. Reduced long bone length and decreased mineral density. | (Laugel-Haushalter et al., 2014; X. Yang et al., 2004) |
| Ets1−/− | Ectopic NCC-derived cartilage in heart, VSD. Rare surviving mouse had white belly spot. Increased apoptosis of melanoblasts. | Perinatal lethal on C57Bl/6 background. | (Gao et al., 2010; Saldana-Caboverde et al., 2015) |
| Srfflox/flox; Wnt1-Cre | Facial cleft, micrognathia, thymic and thyroid aplasia, PTA, VSD, DRG innervation defects. | Background dependent lethality between E13.5 and late gestation. | (Newbern et al., 2008; Vasudevan and Soriano, 2014; Wickramasinghe et al., 2008) |
| P38 LoF | |||
| Mapk14−/− (p38α) | NA | Lethal by E12.5. Anemia, liver, heart, and placenta defects. | (Adams et al., 2000; Allen et al., 2000; Mudgett et al., 2000; Tamura et al., 2000) |
| Mapk14flox/flox; Mapk11−/−; Sox2-Cre (p38α/β) | NA | Lethal by E16.5. Exencephaly, small liver, thin myocardium, VSD. | (del Barco Barrantes et al., 2011) |
| Mapk12/13−/− (p38γ/δ) | NA | Viable and fertile. | (Sabio et al., 2005) |
| Tak1flox/flox; Wnt1-Cre | Cleft palate. | Perinatal lethal. | (Song et al., 2013; Yumoto et al., 2013) |
| JNK LoF | |||
| Mapk8−/− (Jnk1), Mapk9−/− (Jnk2), Mapk10−/− (Jnk3), Mapk8/10−/−, Mapk9/10−/− | NA | Viable and fertile. | (Kuan et al., 1999) |
| Mapk8/9−/− | Normal. | Lethal by E12.5. Exencephaly and neural apoptosis defects. | (Kuan et al., 1999; Sabapathy et al., 1999) |
| Mkk4−/− | NA | Lethal by E14. | (Di Yang et al., 1997; Ganiatsas et al., 1998; Nishina et al., 1999) |
| Mkk7−/− | NA | Viable and fertile. | (Schramek et al., 2011) |
| JNK Effectors | |||
| Jun−/− | Lack of NCCs in cardiac OFT. | Lethal E13. Apoptosis of hepatoblasts and hematopoietic cells. | (Eferl et al., 1999) |
| JunAA/AA | NA | Viable and fertile. Small size, resistant to epileptic seizures and neuronal apoptosis. | (Behrens et al., 1999) |
| ERK5 LoF | |||
| Mapk7−/− (Erk5) | Disorganized cranial mesenchyme, small PAs | Lethal at E10.5. Cardiovascular defects. | (Regan et al., 2002) |
| Mek5−/− | NA | Similar to above. | (Wang et al., 2004) |
| Mapk7flox/flox; Wnt1-Cre | Micrognathia, truncated ear, reduced size. | Viable and fertile. | (Newbern et al., 2011) |
| PI3K LoF | |||
| Pik3ca−/− (p110α) or Pik3caD933A/D933A | NA | Lethal at E10.5. Hemorrhaging, subepidermal blebs, angiogenesis defects. | (Bi et al., 1999; Graupera et al., 2008) |
| Pik3cb−/− (p110β) | NA | Lethal at E3.5. | (Bi et al., 2002) |
| Pik3cbK805R/K805R | NA | Subviable. | (Ciraolo et al., 2008) |
| Pik3cd−/− (p110δ) | NA | Viable with immune defects. | (Jou et al., 2002; Okkenhaug et al., 2002) |
| Pik3r1−/− or Pik3r2−/− | NA | Viable and fertile. | (Brachmann et al., 2005) |
| Pik3r1/2−/− | Facial cleft. | Lethal between E10.5-E12.5. Hemorrhaging, subepidermal blebs, wavy neural tube. | (Brachmann et al., 2005) |
| PI3K GoF | |||
| Ptenflox/flox; Wnt1-Cre | Overgrowth of craniofacial structures. Increased proliferation, enhanced osteoblast differentiation. | Perinatal lethal. | (T. Yang et al., 2017) |
| Ptenflox/flox; Dct-Cre (melanocytes) | Temporary overgrowth of dermal melanocytes. Resistance to graying. | Most mice die within two months of life due to neurologic defects. Small size. | (Inoue-Narita et al., 2008) |
| PI3K Effectors | |||
| Pdk1−/− | Absent PAs and DRG. | Lethal E9.5. No somites or heart, generally delayed. | (Lawlor et al., 2002) |
| Akt1−/− | NA | Viable and fertile. Growth retardation. | (Chen et al., 2001) |
| Akt1−/−, Akt1/2−/− | NA | Perinatal lethal. Dwarfism, skin, muscle, and bone defects. | (Peng et al., 2003) |
| Akt2−/−, Akt3−/−, Akt2/3−/− | NA | Viable and fertile. | (Dummler et al., 2006) |
| Akt1/3−/− | NA | Lethal between E11-E12. Morphologically normal at E10.5. | (Z. Z. Yang et al., 2005) |
| Mkl2−/− (also regulated by other pathways) | Cardiac OFT smooth muscle defect. | Perinatal lethal. | (Li et al., 2005) |
| Rac1flox/flox; Wnt1-Cre | Cleft lip and palate, PTA, ectodermal detachment, reduced proliferation. Possible differentiation defects. Reduced DRG. | Lethal between E12-E13.5. | (Fuchs et al., 2009; Thomas et al., 2010) |
| Cdc42flox/flox; Wnt1-Cre | Cleft lip and palate, shortened snout, PTA, VSD, possible migration defects, reduced proliferation, small DRG. | Lethal between E14.5- birth. | (Fuchs et al., 2009; Liu et al., 2013) |
| Tg(RockDN); Wnt1-Cre | Facial cleft, hypoplastic PAs, shortened snout, OFT defects, cytoskeletal disorganization, increased apoptosis. | Lethality between midgestation and E18.5. | (Phillips et al., 2012) |