Pianp deficiency links GABAB receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior

Abstract

Pianp (also known as Leda-1) is a type I transmembrane protein with preferential expression in the mammalian CNS. Its processing is characterized by proteolytic cleavage by a range of proteases including Adam10, Adam17, MMPs, and the γ-secretase complex. Pianp can interact with Pilrα and the GB1a subunit of the GABAB receptor (GBR) complex. A recent case description of a boy with global developmental delay and homozygous nonsense variant in PIANP supports the hypothesis that PIANP is involved in the control of behavioral traits in mammals. To investigate the physiological functions of Pianp, constitutive, global knockout mice were generated and comprehensively analyzed. Broad assessment did not indicate malformation or malfunction of internal organs. In the brain, however, decreased sizes and altered cellular compositions of the dentate gyrus as well as the cerebellum, including a lower number of cerebellar Purkinje cells, were identified. Functionally, loss of Pianp led to impaired presynaptic GBR-mediated inhibition of glutamate release and altered gene expression in the cortex, hippocampus, amygdala, and hypothalamus including downregulation of Erdr1, a gene linked to autism-like behavior. Behavioral phenotyping revealed that Pianp deficiency leads to context-dependent enhanced anxiety and spatial learning deficits, an altered stress response, severely impaired social interaction, and enhanced repetitive behavior, which all represent characteristic features of an autism spectrum disorder-like phenotype. Altogether, Pianp represents a novel candidate gene involved in autism-like behavior, cerebellar and hippocampal pathology, and GBR signaling.

Survey of disorders of sex development in a large cohort of patients with diverse Mendelian phenotypes

“…For female presentations, 71% (n = 5) included ambiguous genitalia and 2 patients (29%) presented with clitoromegaly, one of 2). We first published PIANP, which encodes a protein that regulates glutamate release in the brain, in the context of intellectual disability (Anazi et al, 2017;Winkler et al, 2019). This previously reported patient (15DG0989) with global developmental delay (GDD) presented with bilateral undescended testes, hypotonia, almond-shaped eyes, tapered fingers, and prominent forehead (Figure 1).…”

Glial Factors Regulating White Matter Development and Pathologies of the Cerebellum

“…The involvement of the cerebellum in higher processes of cognition and emotion [1,2] and its relevance as a locus for a range of disorders and diseases make this simple yet elusive structure an important model in a number of fields. Cellular and anatomical dysfunction of the cerebellum has been associated with psychological disorders, such as autism, attention deficit, hyperactivity or schizophrenia [3][4][5][6][7][8]. In recent years, our understanding of some of the more familiar aspects of cerebellar growth, such as its territorial allocation and the origin of its various cell types, has undergone major recalibration.…”

GABAB receptor inhibits tumor progression and epithelial-mesenchymal transition via the regulation of Hippo/YAP1 pathway in colorectal cancer

“…EMT, an essential regulatory process that mediates invasion and metastasis, is considered a culprit of metastasis in CRC 29 . There are many pathways upstream of EMT, such as Wnt/β-catenin, JNK, and TGF-β 25 , 26 . In this study, the expression of EMT-related molecules N-cadherin and Vimentin were found to be elevated, and E-cadherin was suppressed (at the protein and mRNA level) in GABABR1 knockdown RKO and Lovo cells.…”

“…As an inhibiting neurotransmitter, previous prospective studies on GABABR mainly involved neurons, neuropathic pain and neuroinflammation [23][24][25]. The role of GABABR in cancer has received increasing attention in recent years.…”