Table 2.
Systematic summary of phenotypes in Fe65, APP, and Mena/VASP family KOs.
| Genotype | Viability | Neuronal Migration/Positioning | Outgrowth | Laminin Organization | Synapse Formation | ||||
|---|---|---|---|---|---|---|---|---|---|
|
p97Fe65–/– (↑p60Fe65 [15]) |
normal [15] | n. d. | n. d. | n. d. | n. d. | ||||
| Fe65–/– | normal [167] | n. d. | n. d. | n. d. | ←spine density [169] | ||||
| Fe65L1–/– | normal [167] | n. d. | n. d. | n. d. | ←spine density [169] | ||||
| Fe65–/–/Fe65L1–/– | lower Mendelian frequency [167] |
lissencephaly type II [167] mislocalization of CR neurons [167] ↓CSPGs in marginal zone heterotopias [167] |
↓axonal fibers [167] | ↓in marginal zone heterotopias [167] Altered in MEF cells [167] ↑in lens [168] |
←spine density [169] | ||||
|
APP–/– (↑APLP1 [205], ↑APLP2 [205]) |
normal [206,207,208,209] | impaired axon targeting in retinal ganglion cells [210] impaired axon pruning after whisker plucking in primary somatosensory cortex [211]↑cellular adhesion [212] |
↓axonal fibers [207,209,213] ↓axonal/dendritic outgrowth and branching [212,214,215,216,217,218] |
n. d. | ↓synapse/spine density [212,214,216,217,219,220,221] altered spine plasticity [219,220,221,222,223] |
||||
|
APP–/– APLP1–/–
APLP2–/– |
perinatally lethal [172] | lissencephaly type II [172] rare phenotypes: polymicrogyry, exencephaly [172] disrupted organization and ↓of CR cells [172] disrupted CSPG pattern in marginal zone heterotopias [172] cTKO 1: diffuse patterning of hippocampal layers [224] |
deficits in glia endfoot formation/spanning [172] ↓axonal fibers [172,224] ↓axonal/dendritic outgrowth + branching [224] |
disrupted in marginal zone heterotopias [172] cTKO 1: disrupted in hippocampus but not cortex [224] |
disrupted synaptophysin staining in marginal zone heterotopias [172] cTKO 1: ↓spine density [224] |
||||
| Mena–/– | normal [72] Mena –/– profilin+/–:prenatal lethal [72] |
n. d. | ↓axonal fibers [72,225] Mena –/– profilin +/–: defects in neurulation [72] |
n. d. | n. d. | ||||
|
Mena–/– VASP–/–
EVL–/– |
perinatally lethal [76] | lissencephaly type II [75,76] exencephaly [76] altered cortical intralayer neuron positioning [76] |
deficits in glia endfoot formation [76] ↓axonal fibers [75,76] ↓axonal/dendritic outgrowth [75,76] |
disrupted in marginal zone heterotopia [75,76] | n. d. | ||||
| Genotype | NMJ Formation | Morphological Abnormalities | Behavior and Learning | Electrophysiology | |||||
| p97Fe65–/– (↑p60Fe65 [15]) | n. d. | normal [15] | impaired learning/memory [15,166] | ↓LTP [166] | |||||
| Fe65–/– | ↓pre-/postsynaptic area [169] ↓apposition of pre-/postsynapse [169] ↑fragmentation of postsynapse [169] |
normal [167,169] | subtle muscle weakness [168,169] impaired learning/memory [169] |
↓PTP [169], ←LTP [169], ←PPF [169] | |||||
| Fe65L1–/– | ↓pre-/postsynaptic area [169] ↓apposition of pre-/postsynapse [169] ↑fragmentation of postsynapse [169] |
normal [167,169] except: preliminary stage of cataract [168] |
subtle muscle weakness [168,169] impaired learning/memory [169] |
←PTP [169], ←LTP [169] | |||||
| Fe65–/–/Fe65L1–/– | ↓pre-/postsynaptic area [169] ↓apposition of pre-/postsynapse [169] ↑fragmentation of postsynapse [169] centralized nuclei in muscle fibers [168] |
↓body size [167] lens degeneration [168,169]/cataract [168] ↑ventricle size [167] ↓fimbria size and medial shift [167] |
bilateral circling behavior [167,169] muscle weakness [168,169] impaired learning/memory [169] altered social behavior [169] |
↓PTP [169], ↓LTP [169], ←PPF [169] | |||||
|
APP–/– (↑APLP1 [205], ↑APLP2 [205]) |
Normal [226] | ↓body weight [207,208,227,228] ↓brain weight [213,228] delayed eye opening [208] hypersensitivity to kainate-induced seizures [229] |
muscle weakness [206,207,208,214,228] impaired learning/memory [207,209,214,218,223,227,228] altered social/innate behavior [208,209,228] |
↓PTP [216], ↓LTP [214,216,217,228] ←↓PPF [208,227,230,231], ←mEPSC frequency [218], ←mEPSC amplitude [218], ↓mIPSC frequency [218], ←mIPSC amplitude [218] |
|||||
| APP–/– APLP1–/–APLP2–/– | n. d. | cTKO 1: ←cortical [224,232]/ hippocampal [232] volume |
cTKO 1: impaired learning/memory [224,232] altered social/innate behavior [224] |
cTKO1: ↓LTP [224,232], ↑↓PPF [224,232], ←↑mEPSC frequency [224,232], ←↑mEPSC amplitude [224,232], ←mIPSC frequency [224], ←↑mIPSC amplitude [224] | |||||
| Mena–/– | n. d. | n. d. | n. d. | n. d. | |||||
|
Mena–/–VASP–/–
EVL–/– |
n. d. | exhibit edema [233] enlarged ventricle [76] |
n. d. | n. d. | |||||
1 Conditional triple knockout (TKO) of excitatory forebrain neurons; n. d., not determined; APP, amyloid precursor protein; APLP, APP-like protein; Fe65L, Fe65-like protein; Mena, mammalian enabled; VASP, vasodilator-stimulated phosphoprotein; EVL, Ena-VASP-like protein; CR, Cajal Retzius; CSPGs, chondroitin sulfate proteoglycans; MEF, mouse embryonic fibroblast; LTP, long term potentiation; PTP, post-tetanic potentiation; PPF, paired-pulse facilitation; mEPSC, miniature excitatory postsynaptic current; mIPSC, miniature inhibitory postsynaptic current; ↓, reduction; ↑, increase; ←, no alteration.