Graduation Year

2015

Document Type

Thesis

Degree

M.S.P.H

Degree Name

MS in Public Health (M.S.P.H.)

Degree Granting Department

Public Health

Major Professor

Giffe Johnson, Ph.D.

Co-Major Professor

Raymond D. Harbison, Ph.D.

Committee Member

Michael E. Fant, MD, Ph.D.

Keywords

Brain Defects, NeuN, NF-M, Iba1, Anxiety, Motor Deficiency

Abstract

Placenta-specific 1 (Plac1) is an X-linked gene that is essential for normal placental development. Previous studies have shown that Plac1 is also expressed in the fetal brain and paternally imprinted. Its expression in the fetal brain is markedly downregulated immediately after birth. Plac1 ablation predisposes Plac1-null males and Xm-X Hets (inactive maternal allele) to an increased risk of developing lethal postnatal hydrocephalus suggesting a functional role for Plac1 during embryonic development. The objective of this study was to characterize the effect of Plac1 on brain development and postnatal function. In order to address this, a mutant Plac1 mouse model, established on the C57BL/6J background, was studied. Formalin-fixed, paraffin-embedded whole mount embryos and brain sections were obtained at various stages of development. Plac1 expression was assessed by qRT-PCR and immunohistochemistry (IHC). Brain structure was assessed by histopathological and magnetic resonance imaging (MRI) analysis. Behavioral analysis was conducted using the PhenoMaster automated cage system and a battery of classical behavioral tests. Our results revealed Plac1 expression throughout the embryonic brain when assessed by qRT-PCR and IHC at E16.5 and E18.5. MRI analysis of an adult Plac1 knockout (KO) brain revealed microcephaly (14%), reduced ventricular volume, and increased heterogeneity of the medulla compared to a WT brain. Consistent with these findings, H&E staining of the KO brain revealed a smaller cortical mantle, a dysmorphic hippocampus, and a dysmorphic cerebellum with reduced folia. IHC analyses of NF-M, NeuN, and Iba1 immunostaining revealed significant reductions in axonal and neuronal development and increased activated microglia in KO brain, but not in Xm-X Hets. Although no structural abnormalities were detected in Xm-X Hets, behavioral analyses did reveal reduced activity and behaviors consistent with increased anxiety. In conclusion, Plac1 is a paternally imprinted, X-linked gene that is associated with abnormal brain development, reduced activity, and specific behavioral abnormalities.

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