Phenotypes for Ccdc39 MGI:5056384 MGI Mouse

postnatal lethality, complete penetrance ( J:253968 )

• all homozygotes die within 3 weeks of age

decreased body weight ( J:253968 )

• body weight is significantly decreased at P7-P14

heterotaxia ( J:253968 )

• at P4, 2 of 15 homozygous pups exhibit heterotaxia

right-sided stomach ( J:253968 )

• at P4, 5 of 15 homozygous pups exhibit a right-sided stomach

situs inversus totalis ( J:253968 )

• at P4, 3 of 15 homozygous pups exhibit situs inversus totalis, including dextrocardia

abnormal brain ependyma motile cilium morphology ( J:253968 )

• at P1, TEM analysis revealed that brain ependymal cilia are significantly thinner and show various types of ciliary axonemal microtubule disorganization, including absence of inner dynein arms, mislocalization of one or two microtubule peripheral doublets (MPD), and absence of the central pair (CP); however, outer dynein arms appear normal

• at P1, ~27% of ependymal cilia have lost the CP and show MPD (9+0 plus MPD), 23% have lost MPD (8+2), and 50% show normal CP and MPD (9+2 plus MPD)

• ectopic abnormal ciliary membrane inclusions are occasionally observed

• ependymal cilia exhibit an increased number of gamma-tubulin-stained basal bodies

• at P0, SEM analysis of multi-ciliated ependymal cells on the ventromedial forebrain wall and the central aqueduct wall show significantly shorter, thinner, but more abundant cilia relative to those in wild-type controls

abnormal brain ependyma motile cilium physiology ( J:253968 )

• most ependymal cilia appear largely immobile with virtually undetectable ciliary beat pattern at P1 and P6

• only ~12% of ependymal cilia exhibit rigid and subtle (dyskinetic) movement, resulting in a significantly reduced ciliary beating frequency

abnormal brain development ( J:253968 )

abnormal cortical ventricular zone morphology ( J:253968 )

• the ventricular zone (VZ) region of the telencephalic ventricular wall is significantly smaller at P1

• postnatal neural VZ/SVZ progenitors are significantly reduced at P1 and nearly absent at P5

• however, development of the cerebral cortical layers is normal

hydrocephaly ( J:174027 , J:253968 )

• mice develop progressive hydrocephalus, not present at birth (J:174027)

• early postnatal hydrocephalus appears to arise as a result of defective motile cilia already present at embryonic stages (J:253968)

enlarged brain ventricles ( J:253968 )

• homozygotes exhibit mild ventriculomegaly at P1, but not at E18

dilated lateral ventricle ( J:174027 )

dilated third ventricle ( J:174027 )

small olfactory bulb ( J:253968 )

• olfactory bulbs are smaller

abnormal postnatal subventricular zone morphology ( J:253968 )

• the subventricular zone (SVZ) region of the telencephalic ventricular wall is significantly smaller at P1

• postnatal neural VZ/SVZ progenitors are significantly reduced at P1 and nearly absent at P5

gliosis ( J:253968 )

• whole brain lysates from P10 brains show increased GFAP protein levels, indicating enhanced gliosis

abnormal cerebrospinal fluid flow ( J:253968 )

• ependymal cells with immobile cilia show no evidence of directional CSF movement in the ventricles

• a ~70% decrease in CSF flow speed is noted at both the level of the ventromedial wall of the forebrain and the central aqueduct ependymal cells

• analysis of CSF bulk flow revealed that Evans Blue dye injected into an anterior horn of the lateral ventricle at P8 failed to reach the third and fourth ventricles within 10 min, unlike in control mice

• however, the size/shape of the central aqueduct and the foramen of Monro are normal P8, and no blood or tumor mass are noted at P14, suggesting that CSF flow retardation is not due to physical obstruction

dysmyelination ( J:253968 )

• whole brain lysates from P10 brains exhibit reduced myelin basic protein levels, indicating hypomyelination