All Phenotypes Ulk4<tm1a(KOMP)Wtsi> MGI Mouse

postnatal lethality, incomplete penetrance ( J:234631 )

• mice are born at normal Mendelian ratios but show significant preweaning lethality and rarely survive to P28

decreased body weight ( J:234631 )

• at P12, body weight is reduced by ~30% relative to that in wild-type or heterozygous controls

• however, body weight is normal at P0

postnatal growth retardation ( J:234631 )

• mice exhibit marked growth retardation

domed cranium ( J:234631 )

• all mice exhibit domed-shaped heads 2 weeks after birth

abnormal brain ependyma motile cilium morphology ( J:234631 )

• at P12, brains exhibit fewer and disorganized ependyma cilia or absence of cilia in large areas

• SEM analysis of the LV surface revealed a severe reduction in the number of cilia bundles and a large proportion of ependymal cells with no cilia arrays, suggesting underdevelopment of motile cilia

• TEM analysis showed that, although cilia length is relatively normal at P18, microvilli of smaller and shorter projections are abundant on the ependymal cell surface

• cilia development is delayed as the basal body (BB)-vesicle fusion complex (immature cilium) is still present beneath the ependymal membrane at P18

• BBs are dispersed and randomly orientated, with some adjacent BBs oriented in completely different directions

• BB-vesicle fusion complexes with 90 degree difference to the normal orientation are observed

• at P18, some ependymal cilia display normal 9 + 2 microtubular ultrastructure while others show major defects in axonemal organization including an array of 9 + 0, 8 + 4, and 8 + 0 ultrastructures

• whole-genome RNA sequencing revealed dysregulated expression of Foxj1 (a master switch of ciliogenesis) and numerous other ciliogenesis genes

absent brain ependyma motile cilia ( J:234631 )

• at P12, absence of ependymal cilia is observed in large areas

abnormal brain ependyma motile cilium physiology ( J:234631 )

• ependymal cilia are highly disorganized and randomly scattered on the surface of the LV wall, indicating dysfunctional cilia with no directional beating

abnormal Reissner's fiber morphology ( J:234631 )

• no Reissners fiber (RF) extension is detected at P12, unlike in wild-type controls where RF extends caudally to the aqueduct, fourth ventricle, and spinal cord

• however, the number of SCO cells is not significantly altered

obstructive hydrocephaly ( J:234631 )

• all mice exhibit congenital hydrocephalus with progressive severity during the early postnatal period

• hydrocephalus is associated with subcommissural organ (SCO) dysfunction and aqueduct stenosis

cerebral aqueductal stenosis ( J:234631 )

• at P12, scanning electron microscopy (SEM) revealed aqueduct blockage (stenosis), unlike in wild-type controls

enlarged brain ventricles ( J:234631 )

• mice exhibit ventriculomegaly at P12

dilated brain ventricle ( J:234631 )

• at P0, mice exhibit significant dilation of the lateral and third ventricles

• at P12, the ventricle at the posterior commissural level is 5-fold dilated relative to that in wild-type controls

dilated lateral ventricle ( J:234631 )

• significant dilation of the lateral ventricle (LV) is already noted at P0 but is not as severe as at P12

• at P12, the LV is 17.5-fold larger at the anterior commissural level than that in wild-type controls

dilated third ventricle ( J:234631 )

• significant dilation of the third ventricle (3V) is already noted at P0 but is not as severe as at P12

• at P12, the 3V is 4.7-fold dilated relative to that in wild-type controls

decreased corpus callosum size ( J:211886 )

• partial agenesis of the corpus callosum is noted at P0, with many areas lacking nerve fibers

abnormal cerebrospinal fluid flow ( J:234631 )

• at P12, cerebrospinal fluid (CSF) flow is obstructed in the aqueduct leading to hydrocephalus, unlike in wild-type controls

• whereas injected Evans blue dye is detected in the LV and 3V, little dye reaches the SCO ventricle and no dye is seen in the aqueduct, fourth ventricle (4V) or spinal canal