Michael Molumby and Lisa Harney to Present at Student Seminar 8/23/2016

Michael’s Abstract

The g-Protocadherins interact with neuroligin-1 and inhibit its synaptogenic activity

Michael J. Molumby, Rachel M. Anderson, Dillan J. Newbold, Norah K. Koblesky, Andrew M. Garrett, Dietmar Schreiner, Jason J. Radley, Joshua A. Weiner

The a-, b-, and g-Protocadherins (g-Pcdhs) are cadherin superfamily adhesion molecules encoded by clustered gene families. The 22 g-Pcdhs are combinatorially expressed in the brain, and play critical roles in synaptogenesis, dendrite arborization and patterning, and the survival of subsets of neurons. The g-Pcdhs can interact promiscuously with each other, and with other clustered Pcdhs, in cis, but interact strictly homophilically in trans. Mice lacking the g-Pcdhs in the cerebral cortex exhibit severely reduced dendrite arborization (Garrett, et al., Neuron, 2012). Recently we demonstrated that g-Pcdhs promote dendrite arborization in vivo through local neuron-neuron and neuron-astrocyte homophilic interactions (Molumby et al., Cell Reports, 2016). Though -Pcdhs regulate the progression of spinal cord synaptogenesis (Garrett and Weiner, J. Neurosci., 2009), a role for these molecules in cortical dendritic spines and synapses has yet not been examined.

Here, we provide evidence that the g-Pcdhs negatively regulate synapse formation and spine morphogenesis in forebrain neurons. Mice lacking all -Pcdhs in the cortex exhibit significantly increased spine density in vivo,  while spine density is significantly decreased in mice overexpressing one of the 22 -Pcdh isoforms.  We thus asked whether the -Pcdhs might be inhibitory in an artificial synapse co-culture assay. Indeed, we found that multiple g-Pcdhs can, when co-expressed in COS cells, strongly inhibit the ability of the synaptic cell adhesion molecule neuroligin-1 to promote presynaptic differentiation in contacting axons. The g-Pcdhs physically interact in cis with neuroligin-1 on dendrites of cultured neurons, and can co-immunoprecipitate neuroligin-1 both in vitro and in vivo. We present in vitro evidence that the interaction between -Pcdhs and neuroligin-1 disrupts the latter’s binding to its presynaptic partner neurexin1β.  Additionally, we show that g-Pcdh overexpression in cultured hippocampal neurons suppresses the increase in spine density observed upon neuroligin-1 overexpression.  This work suggests a potential new mechanism by which g-Pcdhs regulate the “choice” between dendrite arbor growth and formation and/or stabilization of dendritic spines and synapses in the developing brain.

Lisa’s Abstract

Identification of a novel, de novo FGFR1 mutation in an individual with Hartsfield Syndrome

Harney, L.A., Bernabe, H., Nidey, N., Standley, J., Schnieders, M., Murray, J.C.

Mutations in FGFR1 have recently been associated with Hartsfield Syndrome, a disease with the rare combination of holoprocencephaly (HPE) and ectrodactyly (EEC). Here we report a novel, de novo mutation in FGFR1 in a previously unsolved clinical case of multiple congenital anomalies. The proband presented with bilateral cleft lip and palate, malformed auricles and bilateral EEC of his hands and feet at birth. He was later diagnosed with diabetes insipidus, spastic quadriplegia, developmental delay, and agenesis of the corpus callosum. Microarray analysis resulted in an unremarkable copy number variant profile. Although this exact combination of clinical features has not been reported in a patient to date, we noted phenotypic overlap with individuals with Hartsfield Syndrome. Sequencing of FGFR1 identified a novel and previously unreported de novo mutation in exon 11 (p.G487C), resulting in the diagnosis of Hartsfield Syndrome for this individual.


Posted on August 19, 2016, in Student Seminar. Bookmark the permalink. Leave a comment.

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