Large-scale microarray data [ 16] enabled us to examine the statistical significance of the enrichment of the system-level function categories among the AIS subfamilies and revealed that the most significantly enriched category among the AIS subfamilies was NS.
The VDE system which integrates the function of AIS, ASM, and VDE was also introduced by the International Association of Lighthouse Authorities (IALA) [4].
Information regarding the NS- and AIS-related functions of human genes in the AIS subfamilies was assigned on the basis of published literature (Dec 2006).
Indeed, the disruption of the molecular organization, altered ion channel expression, function, location, and/or density at the AIS are emerging as key players in the pathophysiology of neurological disorders [reviewed in (Buffington and Rasband, 2011)].
Regarding the involvement of HDAC6 in the regulation of the axon initial segment (AIS), a highly important structure for the axonal identity and neuronal function [16], [48], we show that the AIS microtubules resistant to detergent extraction are highly acetylated.
We then assigned a system-level function category to an AIS subfamily if the AIS subfamily included at least one member gene having the system-level function category.
Several studies also suggested a strong correlation between the degree of thoracic hypokyphosis and the decrease of pulmonary function in AIS patients [ 23- 25].
This analysis revealed that the NS category was significantly over-represented as an ancestral function among AIS subfamilies, supporting statistically the hypothesis [ 22] that AIS-related signaling genes were ancestrally involved in the development and/or function of the NS in urbilaterians.
In 4.1B-/ mice, some Kv1 channels are found in the JXP-AIS (probably resulting from a weak barrier function at the para-AIS), where they might still be stabilized by 4.1B-independent mechanisms, as in the AIS.
Our outgroup comparison analysis suggested the category NS as the ancestral function of most AIS genes (Table 2), as in a previous study [ 22].
