Intrauterine growth restriction compromises cerebellar development by affecting radial migration of granule cells via the JamC/Pard3a molecular pathway

• Published in: Experimental neurology Vol. 336; p. 113537
• Main Authors: Iskusnykh, Igor Y., Fattakhov, Nikolai, Buddington, Randal K., Chizhikov, Victor V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2021
• Subjects: Animals; Animals, Newborn; Apoptosis; Cell Count; Cell Differentiation; Cell Movement; Cell Proliferation; Cerebellar hypoplasia; Cerebellum; Cerebellum - growth & development; Cerebellum - pathology; Cytoplasmic Granules; Development; Developmental brain disorder; Female; Fetal Growth Retardation - pathology; Intrauterine growth restriction; Neurogenesis; Neuronal migration; Pig; Pregnancy; Proliferation; Purkinje Cells - pathology; Signal Transduction - genetics; Swine; Translational large animal model; Cerebellum; OCT; NGA; Proliferation; EGL; SGA; Neurogenesis; Cerebellar hypoplasia; Pig; IGL; Intrauterine growth restriction; Neuronal migration; IUGR; Developmental brain disorder; GCs; LCM; Development; Translational large animal model; Apoptosis
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2020.113537

Intrauterine growth restriction (IUGR) affects ~10% of human pregnancies, results in infants born small for gestational age (SGA), and is associated with motor and cognitive deficits. Human studies suggest that some deficits in SGA patients originate in the cerebellum, a major motor-coordination and cognitive center, but the underlying mechanisms remain unknown. To identify the cerebellar developmental program affected by IUGR, we analyzed the pig as a translational animal model in which some fetuses spontaneously develop IUGR due to early-onset chronic placental insufficiency. Similar to humans, SGA pigs revealed small cerebella, which contained fewer mature granule cells (GCs) in the internal granule cell layer (IGL). Surprisingly, newborn SGA pigs had increased proliferation of GC precursors in the external granule cell layer (EGL), which was associated with an increased density of Purkinje cells, known to non-autonomously promote the proliferation of GCs. However, the GCs of SGA pigs did not properly initiate exit from the EGL to IGL, which was associated with a decreased density of guiding Bergmann glial fibers, reduced expression of pro-migratory genes Pard3a, JamC and Sema6a, and increased apoptosis. While proliferation spontaneously normalized during postnatal development, accumulation of pre-migratory GCs and apoptosis in the EGL were long-lasting consequences of IUGR. Using organotypic cerebellar slice cultures, we showed that normalizing expression of Pard3a and JamC, which operate in the same molecular pathway in GCs, was sufficient to rescue both migratory and, at a later time point, apoptotic defects of IUGR. Thus, a decreased exit of GCs from the EGL, due to disrupted Pard3a/JamC radial migration initiation pathway, is a major mechanism of IUGR-related cerebellar pathology.
•IUGR reduces the number of mature granule neurons in the cerebellum.•IUGR increases apoptosis and delays migration of granule cells from the EGL.•IUGR reduces expression of pro-migratory genes JamC, Pard3a, and Sema6A in the EGL.•JamC/Pard3a rescue migration and apoptosis of granule cells in the IUGR-affected cerebellum.