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Table 2 RASopathy mouse models and their phenotypes

From: The impact of RASopathy-associated mutations on CNS development in mice and humans

Gene Mouse model CNS structural phenotypes Other phenotypes
Nf1 Nf1 homozygous knockout Defects in the neural tube, hyperplasia of neural crest-derived ganglia [75] Embryonic lethality, heart defects, delay in organ development [76, 77]
Nf1 heterozygous knockout Increased number of astrocytes [78, 79] Impaired synaptic plasticity, impaired spatial learning, heart defects [80,81,82]
Synapsin 1-dependent Nf1 ablation Reduced size and weight of the forebrain, reduced cortical thickness, increased astrogliogenesis [83] Learning deficits, growth retardation [83, 84]
hGFAP-dependent Nf1 ablation Increased gliogenesis, enlarged cerebral cortex, defective GNP migration and proliferation
[85,86,87,88]
Postnatal lethality, growth retardation [86, 87]
BLBP-dependent Nf1 ablation Increased glial lineage proliferation, abnormal neuronal differentiation [89] Postnatal lethality [89]
Nestin-dependent Nf1 ablation (induction in adulthood) Unlocked latent oligodendrocyte lineage, defective GNP proliferation and migration, increased adult hippocampal neurogenesis [88, 90, 91] Spontaneous antidepressive-like behavior [91]
Ptpn11 Nestin-dependent Ptpn11 ablation Decreased neural stem cell proliferation, lamination defects, reduced number of neurons, increased number of astrocytes [92] Postnatal lethality, growth retardation [92]
Olig1-dependent Ptpn11 ablation Decreased number of oligodendrocyte precursors and mature oligodendrocytes, reduced axonal myelination [93] Developmental abnormalities [93]
Olig2-dependent Ptpn11 ablation Decreased number of oligodendrocyte precursors, hypomyelination [94] Postnatal lethality, severe shivering [94]
Olig2-dependent Ptpn11Q79R knock-in Increased number of oligodendrocyte precursors, abnormal myelination [94] Not described
Nestin-dependent Ptpn11E76K knock-in Hydrocephalus, aberrant development of ependymal cells, reduced proliferation, enhanced glial differentiation [95] Postnatal lethality, dome-shaped head, reduced anxiety behavior, hyperactivity, impaired motor function [95]
Ptpn11D61G herozygous knock-in Increased neurogenesis, decreased gliogenesis [96] Impaired synaptic plasticity, impaired spatial learning, short stature, craniofacial dysmorphia [97, 98]
Kras Synapsin1-dependent KrasG12V knock-in Enhanced GABAergic synaptogenesis [99] Increased inhibitory tone, impaired spatial learning [99]
Hras HrasG12V homozygous knock-in Hypertrophy of the brain and pyramidal neurons [100] Impaired spatial learning, facial dysmorphia, cardiac defects [100]
aCaMKII-dependent HrasG12V knock-in Increase in docked vesicles [101] Increased synaptic plasticity, enhanced spatial learning [101]
Braf Nestin-dependent Braf ablation Impaired neuronal differentiation, dysmyelination, defective oligodendrocyte differentiation [102, 103] Postnatal lethality, growth retardation, defective motor coordination, neuromuscular defects [102, 103]
BrafV600E heterozygous knock-in Increased number of GFAP positive cells in the DG [104] Reduced life span, growth retardation, facial dysmorphia, cardiomegaly, epileptic seizures [104]
Raf1 Raf1 heterozygous knockout Small granule cell volume, increased cell death, reduced neuronal maturation [105] Postnatal lethality, growth retardation, apoptosis in the lung and liver, limbs coordination problems [106]
Raf1L613V heterozygous knock-in Increased density of astrocytes, enhanced OPCs density [107] Enhanced learning and memory [107]
Mek1/2 Mek1Y130C homozygous knock-in Increased astrocyte density, increased number of cortical oligodendrocytes [108] Pulmonary artery stenosis, cranial dysmorphia [108]
Nestin-dependent Mek1/2 ablation Decrease of astrocyte precursors and OPCs, failure of gliogenesis [109] Early postnatal lethality [109]
hGFAP-dependent Mek1/2 ablation Suppressed generation of astrocyte precursors and OPCs, failure of gliogenesis [109] Postnatal lethality [109]
hGFAP-dependent Mek1S218E,S222E Increase in astrocyte precursors and mature astrocytes, reduction of neuron number [109] Not described
  1. hGFAP Human glial fibrillary acidic protein, BLBP Brain lipid binding protein, GNP Granule neuron progenitor, DG Dentate gyrus, OPCs Oligodendrocyte progenitor cells