409
(Harris et al. 2003 ; Ma et al. 2008 ; Mackenzie and Raible 2012 ). The rate of regeneration was delayed by one or more days when the larvae were treated with cisplatin
or higher concentrations of copper, suggesting that the time course of regeneration
is dependent upon the severity of the ototoxic insult (Mackenzie and Raible 2012 ).
In fact, high concentrations of ototoxins can damage hair cells and supporting cells,
which can proliferate and differentiate into new hair cells (Olivari et al. 2008 ).
There may be a selective advantage for lateral line hair cells to regenerate more
rapidly than inner ear hair cells because the external placement of lateral line hair
cells exposes them more intensely to chemical and mechanical stressors.
As a major impetus for sensory hair cell research in fi sh is to fi nd potential
therapeutics for human hearing loss and its prevention, an understanding of hair
cell death and regeneration signal-transduction pathways is necessary. Although a
full discussion of this topic is beyond the scope of this review, several central
points will be briefl y mentioned. Microarray, microRNA, and next-generation
sequencing (NGS) techniques enable the characterization of gene expression in
fi sh auditory sensory tissues under various experimental conditions and facilitate
identifi cation of the molecular effectors of sensory hair cell regeneration (reviewed
in Smith and Rajadinakaran 2013 ). Many of the molecules and pathways implicated in fi sh hair cell death and recovery are found in humans as well. For example,
hair cell death in zebrafi sh is modulated by c-jun N-terminal kinase (JNK; Ou et al.
2006 ) and both caspase dependent (Cunningham et al. 2002 ; Cheng et al. 2003 )
and independent pathways (Jiang et al. 2006 ), which are also regulated in mammalian models (Cheng et al. 2005 ). Pathways regulated in zebrafi sh during hair
cell regeneration include Wnt/β-Catenin, Notch, Sox2 and Rb (Ma et al. 2008 ;
Millimaki et al. 2010 ; Aman et al. 2011 ; Lin et al. 2013 ). These and other pathways
have recently been reviewed more thoroughly elsewhere (Smith and Rajadinakaran
2013 ; Lush and Piotrowski 2014 ).
8 Future Research Directions
Considerable progress has been made in the last two decades towards advancing our
understanding of the causes and consequences of sensory hair cell loss in fi shes.
The use of zebrafi sh as a biomedical model of sensory hair cell death and regeneration has grown exponentially. Using zebrafi sh high-throughput methods, mutations
affecting inner ear development have been found that are relevant to human hearing
loss (Malicki et al. 1996 ; Whitfi eld et al. 2005 ), numerous pharmaceutical agents
have been tested for ototoxicity (reviewed in Coffi n and Ramcharitar 2015 ; Coffi n
and Ramcharitar 2015 ), and otoprotective compounds have been identifi ed (Coffi n
et al. 2010 , 2013 ). In addition, many pathways involved in sensory hair cell death
and regeneration have been discovered (Smith and Rajadinakaran 2013 ). In the
future, specifi c cellular mechanisms involved in hair cell death and regeneration
will need to be elucidated further, and many of the ototoxic and otoprotective compounds discovered will need to be tested in mammalian models before use in human
Causes and Consequences of Sensory Hair Cell Damage and Recovery in Fishes
(Harris et al. 2003 ; Ma et al. 2008 ; Mackenzie and Raible 2012 ). The rate of regeneration was delayed by one or more days when the larvae were treated with cisplatin
or higher concentrations of copper, suggesting that the time course of regeneration
is dependent upon the severity of the ototoxic insult (Mackenzie and Raible 2012 ).
In fact, high concentrations of ototoxins can damage hair cells and supporting cells,
which can proliferate and differentiate into new hair cells (Olivari et al. 2008 ).
There may be a selective advantage for lateral line hair cells to regenerate more
rapidly than inner ear hair cells because the external placement of lateral line hair
cells exposes them more intensely to chemical and mechanical stressors.
As a major impetus for sensory hair cell research in fi sh is to fi nd potential
therapeutics for human hearing loss and its prevention, an understanding of hair
cell death and regeneration signal-transduction pathways is necessary. Although a
full discussion of this topic is beyond the scope of this review, several central
points will be briefl y mentioned. Microarray, microRNA, and next-generation
sequencing (NGS) techniques enable the characterization of gene expression in
fi sh auditory sensory tissues under various experimental conditions and facilitate
identifi cation of the molecular effectors of sensory hair cell regeneration (reviewed
in Smith and Rajadinakaran 2013 ). Many of the molecules and pathways implicated in fi sh hair cell death and recovery are found in humans as well. For example,
hair cell death in zebrafi sh is modulated by c-jun N-terminal kinase (JNK; Ou et al.
2006 ) and both caspase dependent (Cunningham et al. 2002 ; Cheng et al. 2003 )
and independent pathways (Jiang et al. 2006 ), which are also regulated in mammalian models (Cheng et al. 2005 ). Pathways regulated in zebrafi sh during hair
cell regeneration include Wnt/β-Catenin, Notch, Sox2 and Rb (Ma et al. 2008 ;
Millimaki et al. 2010 ; Aman et al. 2011 ; Lin et al. 2013 ). These and other pathways
have recently been reviewed more thoroughly elsewhere (Smith and Rajadinakaran
2013 ; Lush and Piotrowski 2014 ).
8 Future Research Directions
Considerable progress has been made in the last two decades towards advancing our
understanding of the causes and consequences of sensory hair cell loss in fi shes.
The use of zebrafi sh as a biomedical model of sensory hair cell death and regeneration has grown exponentially. Using zebrafi sh high-throughput methods, mutations
affecting inner ear development have been found that are relevant to human hearing
loss (Malicki et al. 1996 ; Whitfi eld et al. 2005 ), numerous pharmaceutical agents
have been tested for ototoxicity (reviewed in Coffi n and Ramcharitar 2015 ; Coffi n
and Ramcharitar 2015 ), and otoprotective compounds have been identifi ed (Coffi n
et al. 2010 , 2013 ). In addition, many pathways involved in sensory hair cell death
and regeneration have been discovered (Smith and Rajadinakaran 2013 ). In the
future, specifi c cellular mechanisms involved in hair cell death and regeneration
will need to be elucidated further, and many of the ototoxic and otoprotective compounds discovered will need to be tested in mammalian models before use in human
Causes and Consequences of Sensory Hair Cell Damage and Recovery in Fishes