Adnp regulates axogenesis and dendritogenesis in the developing cortex

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Project Summary/Abstract Mutations in Activity-dependent neuroprotective protein (ADNP) lead to “ADNP syndrome” which is characterized by a variety of developmental deficits including mild to severe intellectual disability (ID), Autism spectrum disorder (ASD), epilepsy, speech and motor delay, brain abnormalities, and behavioral problems. Although pathogenic mutations in ADNP are well characterized, the etiology of ADNP syndrome remains elusive and subsequently there are no treatments for this disorder. Truncating and frameshift mutations occur along the length of ADNP and are hypothesized to lead to loss of function. To understand how loss of Adnp affects brain development, it is important to define Adnp’s cellular functions, particularly in early stages upon which sequential stages rely. Neuritogenesis is an early foundational stage of brain development which when disrupted, can lead to systems level changes in functional connectivity. Functional connectivity is often disrupted in disorders that share symptomology with ADNP syndrome. Thus, changes in neuritogenesis and functional connectivity are of interest when uncovering the etiology of ADNP syndrome. Our preliminary data suggest Adnp is an important regulator of cortical neurite formation in layer 2/3 pyramidal neurons, with loss of Adnp resulting in a variety of morphological changes including increased basal dendrite number but decreased length, and increased axon length. We hypothesize that these morphological changes have pathological effects on functional cortical connectivity. Our preliminary data suggest that Adnp regulates axo- and dendritogenesis by promoting MT polymerization and regulating MT sliding. This proposal aims to uncover the details of this cellular mechansim. We will also assess whether these roles influence cortical connectivity. Furthermore, we will determine the consequences of Adnp knockdown on these cellular functions to better understand ADNP syndrome disease etiology. These goals will not only allow us to gain a more complete understanding of Adnp’s roles during cortical development and the etiology ADNP syndrome, but will also allow for the identification of potential therapeutic targets.