Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons

Abstract

BackgroundThe development of neural circuits within the embryonic cerebral cortex relies on the timely production of neurons, their positioning within the embryonic cerebral cortex as well as their terminal differentiation and dendritic spine connectivity. The RhoA GTPases Rnd2 and Rnd3 are important for neurogenesis and cell migration within the embryonic cortex (Nat Commun 4:1635, 2013), and we recently identified the BTB/POZ domain-containing Adaptor for Cul3-mediated RhoA Degradation family member Bacurd2 (also known as Tnfaip1) as an interacting partner to Rnd2 for the migration of embryonic mouse cortical neurons (Neural Dev 10:9, 2015).FindingsWe have extended this work and report that Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd2 and Rnd3 in vitro. Given that these genes are expressed during cortical development, we performed a series of in utero electroporation studies in mice and found that disruptions to Bacurd1/Kctd13 or Bacurd2/Tnfaip1 expression impair the long-term positioning of E14.5-born cortical neurons within the postnatal (P17) mouse cerebral cortex. We also find that forced expression of Bacurd1/Kctd13 and Bacurd2/Tnfaip1 alters the branching and dendritic spine properties of layer II/III projection neurons.ConclusionsWe identify Bacurd1/Kctd13 and Bacurd2/Tnfaip1 as interacting partners to Rnd proteins which influence the development of cortical neurons. Their neurodevelopmental functions are likely to be relevant to human brain development and disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-016-0062-1) contains supplementary material, which is available to authorized users.

Rnd3-induced cell rounding requires interaction with Plexin-B2

“…A potential interaction of Rnd3 with BACURD3, identified in our yeast two-hybrid screen, might promote degradation of inactive RhoA. Intriguingly, BACURD1 and BACURD2 have recently been reported to interact with Rnd2 and Rnd3 (Gladwyn-Ng et al, 2016). …”

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

“…33,76 Consistently, genetic deletion of the entire Kctd13 gene has resulted in increased RhoA expression, the loss of dendritic spines and reduced synaptic activity in the CA1 region of the hippocampus. 11,76 Reduced synaptic transmission is normalized by pharmacological inhibition of RhoA.…”

“…Protein BTB structure Degrades c-Myc 29 Regulates sleep 86 Low in patient-derived glioma stem cells 29 Gen vars assoc. with Alzheimer's risk (GWAS) 110 Degrades RhoA 33,76 Regulates apoptosis 120 Inhibits NF-κB and AP-1 118 Aa a tumor suppressor in nonsmall cell lung cancer 121 Poor prognosis if overexpressed in breast cancer 122 Overexpressed in osteosarcoma 123 16,96 ) Inhibits mTORC1 activity 14 Inhibits Hh pathway by degrading HDAC 12 Deletion/ reduced expression in medulloblastoma 94 Loss of heterozygosity in prostate adenocarcinoma 129 Reduced expression in hepatocellular carcinoma 130 (Continues) Inhibits transcription factor AP-2α 9 and Wnt signaling by degrading β-catenin 131 I27N mutation caused kidney dysfunction in mice 132 Missense mutations associated with scalp-ear-nipple syndrome 133 Other Regulates GABA B2 signaling 17,135,136 ND Other KCNRG ND Kv channel 139,140 Suppresses K + channel activity 139 Deleted in B-cell chronic lymphocytic leukemia, [140][141][142] prostate cancer 140 and multiple myeloma 142 Other KCTD18 ND ND ND Duplication of 2q33 in one patient with epilepsy, devel. delay, autistic behavior 143 Haplotype associated with restless legs syndrome 144 G KCTD20 ND ND Activates Akt 145,146 Gen var associated with insulin resistance (GWAS) 147 BTBD10 ND Akt1-3 148 Inhibits apoptosis, activates Akt 149,150 Sporadic amyotrophic lateral sclerosis 151…”

Recent Advances in the Genetics of Schizophrenia

“…They also show reciprocal effects on head circumference [40] visual evoked potential amplitude [41] and BMI phenotypes [42]. It has been suggested that the major driver of the neuroanatomical phenotypes may be the gene KCTD13 which has been implicated in long-term positioning and dendritic maturation of cerebral cortical neurons [43]. A more distal and smaller region on 16p11.2 has also been implicated in schizophrenia when deleted [44, 45], as well as in developmental delay and obesity [45].…”