Human Molecular Genetics 2004 13(Review Issue 2):R289-R296; doi:10.1093/hmg/ddh249
Human Molecular Genetics, Vol. 13, Review Issue 2 © Oxford University Press 2004; all rights reserved
The developmental genetics of auditory hair cells
R. David Hawkins and
Michael Lovett*
Division of Human Genetics, Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, USA
Received June 15, 2004; Accepted July 27, 2004
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ABSTRACT
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Loss of auditory hair cells (AHCs) is a major cause of human
deafness. Considerable effort has been devoted to unraveling
how these mechanotransducers of sound are specified, with a
view to correcting hearing loss by gene or stem cell therapies.
Recent work on signaling cascades, particularly lateral inhibition
and planar cell polarity, has begun to tie together some of
the known pathways. Mutations in mice and humans that cause
hearing and/or balance disorders are also shedding light on
how AHCs are specified and, maintained and handle ion flux.
Studies on some of these genes are beginning to provide insights
into the more complex genetics of later onset forms of hearing
loss. Progress has also been made in solving some long-term
goals of auditory biology. Cadherin23 has been identified as
a component of AHC stereocilia tip links, and progress has been
made towards identifying the elusive AHC mechanoreceptor channel.
Preliminary steps have also been taken towards inner-ear gene
therapy, and in the engineering of embryonic stem cells for
eventual cell therapies. Mammals cannot regenerate AHCs, but
birds and other lower vertebrates can. Genomic tools have now
been brought to bear on this problem with the aim of deciphering
the molecular basis of this regenerative capability. The combination
of new genomic tools and the many mouse and chicken embryological
and genetic resources should increasingly provide new insights
into how AHCs are programed and maintained.
Congenital hearing loss affects about one in every 500 newborns. However, this comprises only a small proportion of total hearing loss. Approximately 10% of the human population have significant later onset hearing impairment, and the vast majority of this is due to sensorineural hearing loss, resulting from damage to auditory hair cells (AHCs) or their innervation (web site of the National Institute on Deafness and Other Communication Disorders: http:///www.nidcd.nih.gov/health/statistics/hearing.asp). We are born with a few thousand AHCs, which are specialized and essential mechanoelectrical transducers of sound that must be retained in good working order for many decades, because we (and all mammals studied to date) cannot regenerate them. Consequently, considerable effort has been devoted to unraveling how AHCs are specified, with a view to correcting hearing loss by gene or stem cell therapies.
There is a vast literature on the anatomy and developmental genetics of the inner ear. In this review, we deal only with those events that appear to directly impact upon AHC production and maintenance. After a brief description of AHC development, we describe some of the known genetic pathways that function in hair cell development and recent insights into how they may fit together. We then discuss attempts to either discover stem cells or engineer embryonic stem (ES) cells towards an AHC fate. Finally, we discuss more global, genomics-based approaches to pathway discovery and manipulation of hair cell regeneration.
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DEVELOPMENTAL ANATOMY OF AHCs
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Much of our current knowledge of the inner ear is derived from
studies in mouse and chicken (see later). Figure
1 shows some
of the steps in the developmental anatomy of these complex structures.
In mouse,
bona fide AHCs are not discernible until quite late
in development (
E13) and they acquire mechanotransduction between
E16 and E17 (
2). They arise, as do their surrounding supporting
cells (SCs), from a sensory primordium. Eventually, two distinct
types of hair cells are formed in the organ of Corti within
the cochlea, a single row of inner hair cells (IHCs) and three
rows of outer hair cells (OHCs). The hair cells, together with
their surrounding SCs constitute the sensory epithelia (SE).
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Figure 1. Developmental anatomy of the mouse inner ear. (A) Diagram of an embryonic day 8 mouse embryo. All of the structures of the inner ear arise from a small ectodermal thickening (the otic placode), highlighted in red. (B) Diagrams of the structure of the dissected inner ear at days 10–15 of embryogenesis [modified from Morsli et al. (1)]. Dorsal is to the top and anterior is to the right. The areas destined to become the cochlea are shown in blue. By E13 hair cells are beginning to differentiate, by E15 they are starting to acquire mechanotransduction capabilities. (C) Diagram of part of the organ of Corti within the adult cochlea. Four rows of AHCs are surrounded by SCs and have sterocilia imbedded into the overlying tectoral membrane (shown in green). The single row of IHCs is shown in red, and the three rows of OHCs are shown in yellow. Movement of the basilar membrane (triggered by a sound wave) below the hair cells (data not shown) results in hair cell movement and sterocilia deflection.
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In chicken, the arrangement of AHCs and SCs is somewhat different,
but the most striking difference in birds (and other lower vertebrates)
is that, if their AHCs are damaged, they can regenerate new
ones from a population of supporting stem cells (
3–
5).
Discovering the molecular basis of this regenerative capability
has been a major goal of auditory research for almost two decades.
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NOTCH SIGNALING
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The
Notch and
Wingless signaling cascades are important regulators
of lateral inhibition. This occurs when one cell sends an inhibitory
signal to its neighbor, preventing it from taking on the same
fate. Figures
2 and
3 summarize a large body of work from the
late 1990s showing that various components of the Notch pathway
are important in AHC development. For example, in mouse, the
loss of the
Notch ligand
Jagged2 leads to two rows of IHCs and
four rows of OHCs (
7).
Jagged2 appears to be necessary for lateral
inhibition in SCs, expressing
Notch1, to prevent the differentiation
of excess AHCs.
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Figure 2. The Notch and Math1 signaling cascades and the phenotypes of various knockdowns, knockouts or overexpression constructs. This figure summarizes work on mouse and zebrafish AHC phenotypes. The figure shows outer hair cells (OHCs), pillar cells (PCs) and inner hair cells (IHCs) as seen from above. (A)–(F) list the specific genes and the types of alterations (e.g. –/– indicates a homozygous null). In each case, the effect upon AHCs is shown to the right and summarized at the far right. GER is the greater epithelial ridge. Genes are color coded according to the cell type within which they appear to be expressed. Blue is AHC-specific and red is SC-specific. (G)–(I) shows the effects of specific genes on the zebrafish sensory patch of AHCs. References are as follows: Notch1 and Jagged1 antisense knockdowns in rat explants cultures (6). Jagged2 homozygous null mice (7). Jagged1 dominant missense mutation from an ENU screen (8). Hes1 homozygous null mice (9,10). Hes5 homozygous null mice (11). Math1 overexpression in rat explant cultures (11), and adenoviral mediated in vivo overexpression in guinea pigs (12). In the zebrafish an increase of hair cells in the sensory patch is seen for dominant negative alleles of deltaA (13) and 10-fold more hair cells in the mind bomb mutant (14).
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Figure 3. An SC (red) and a HC (blue) are shown. Next to each cell is a list of color coded genes from the Math1 or Notch pathways that are specifically active in one or other cell type. In the lower part of the figure various interactions between components of these pathways are shown. Again, the genes are color coded according to cell type. Ligands and receptors are also color coded with the red and blue vertical lines indicating the SC and AHC cell surfaces, respectively. Lines ending with an arrow indicate induction, lines ending with a perpendicular line indicate repression. For a detailed review on Notch1, its ligands (Delta1, Jagged1 and Jagged2) and effectors (Hes1 and Hes5) see (15). See the text for specifics on the interaction between Math1 and Notch pathways. Math1 is capable of positive autoregulation (16) and negative autoregulation (17) and this is shown in the figure. It is also inhibited directly by Zic1 (18) and either directly or indirectly by Hes1 and Hes5 (6,10,17).
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The expression of
Delta1, another ligand of
Notch, demarcates
those cells that give rise to differentiating AHCs in chickens
and mice (
19,
20).
Delta1 expression in these nascent AHCs is
eventually lost as the cells commit to their fate.
Delta1 is
also expressed during AHC regeneration in the inner ear of chicken
(
21). Recently, Itoh
et al. (
22) have added another piece
to this complex pathway. They demonstrated that the zebrafish
mind bomb locus (which affects numbers of hair cells) encodes
a ubiquitin ligase that specifically acts upon DELTA1, targeting
it for degradation.
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MATH1
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The transcription factor (TF)
Math1 is specifically expressed
in developing AHCs.
Math1 knockout mice fail to produce any
AHCs (
23). In addition, overexpression of
Math1 leads to supernumerary
hair cells. Recent work on the effects of
Math1 in other cell
types has provided additional candidate downstream effectors
for this pathway. For example, three transcription factors,
Lh2A(
LHX2),
Lh2B(
LHX9) and
Barhl1, are no longer expressed in
specific neuronal cell types in
Math1 null mice (
24). The TF
Zic1 was recently shown to act as a repressor of Math1 in the
developing nervous system (
18). Additional
Zic family members
(e.g.
Zic2) are expressed in the inner ear (
25) and during avian
HC regeneration (unpublished data).
Recent evidence indicates that the Notch and Math1 pathways intersect. The TF gene Hes1 is downstream in the Notch pathway (26) and suppresses the Math1 overexpression phenotype of supernumerary hair cells when it is co-transfected into explants (9). Hes1 appears to be a negative regulator of Math 1. Although loss of Hes1 leads to an increase in IHCs, loss of Hes5, a closely related member of the same TF gene family, leads to an increase in OHCs (10). Most recently, Gazit et al. (17) have directly demonstrated (albeit in a different cell type) that Math1 binds to the Hes5 promoter, thereby directly tying together these two important pathways. They propose that Math1 activates Hes5, which in turn inhibits Math1 expression (Figs 2 and 3).
Zheng and Gao (11) first showed that overexpression of Math1 could lead to ectopic hair cells in rat cochlear explants, at least as measured by surrogate hair cell markers such as Myosin7a or immature stereocilia bundles. More recently, Kawamoto et al. (12) have shown that Math1 overexpression in vivo has the same effect in the guinea pig inner ear. This study could not detect whether new hair cells arose in the sensory epithelium, but the putative new hair cells were able to attract axons. These first steps towards inner ear gene therapy are exciting and encouraging and many groups are pursuing these strategies towards eventual hair cell replacement.
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CYCLIN DEPENDENT KINASE INHIBITORS
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Cyclin dependent kinases regulate transition through the cell
cycle, whereas production of cyclin dependent kinase inhibitors
(CKIs) leads to an exit from the cell cycle. Exit from the cell
cycle coincides with the expression of cyclin dependent kinase
inhibitor
P27/Kip1 in the developing mouse organ of Corti between
E12 and E14 (
27). P27/Kip1 appears to be present in SCs, but
absent in AHCs. Homozygous
p27/Kip1 knockout mice have supernumerary
AHCs (both IHCs and OHCs), but they also retain SCs, indicating
that this gene has some role in proliferation (would seem to
have a role in suppressing AHCs), but not an absolute role in
differentiation. Interestingly, heterozygote
p27/Kip1 knockouts
only have additional IHCs. Although
p27/Kip1 expression is one
marker of SCs in the cochlear sensory epithelia, another cell
cycle kinase inhibitor is specific to hair cells.
Ink4d/p19 is expressed in a similar temporal pattern to
p27/Kip1 before
AHC and SC differentiation (
28). However,
Ink4d/p19 knockout
mice do not exhibit obvious morphological defects during embryonic
development. At about 5 weeks after birth the mice show signs
of progressive hearing loss, caused by AHCs reentering the cell
cycle and dying through apoptosis.
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PAX–EYA–SIX–DACH GENES
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The
Pax,
Eya,
Six and
Dach gene families are important in otic
development, but defining how they fit together has proved difficult.
The recent derivation of
Six1 null mice is one step towards
determining the complex epistatic relationships between these
TF gene families (
29,
30).
Six1 expression is lost in
Eya1 nulls
(
29), which appears to place it downstream of
Eya1. However,
the relationship of
Pax genes to
Six and
Eya expression is less
clear. This may reflect functional redundancy in
Pax genes [e.g.
Pax5 and
Pax2 (
31)]. Likewise,
Dach1 does not appear to be simply
downstream of
Pax2 or
Eya1 (
32), unlike the situation in
Drosophila. Defining these connections and functional redundancies is a
continuing challenge.
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GENES THAT AFFECT PLANAR CELL POLARITY
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As AHCs differentiate they reorient to their final arrangement
(
33). The correct coordination of these reorientation events
is necessary for hearing, and this process can be disrupted
by perturbations in
Wnt signaling. At least eight
Wnt genes
are expressed in the organ of Corti. The primary receptors for
these ligands are Frizzled proteins.
Frizzled genes are expressed
in the developing chick ear (
34), but not all the
Frizzled genes
are necessary for this process. These types of orientation defects
can also be caused by other genes that affect planar cell polarity
(PCP). Mouse mutants in
Vangl2 (the ortholog to
Drosophila strabismus/van gogh) and in
Scrib1 (
35) have orientation defects in all rows
of AHCs.
Protein tyrosine kinase 7 (
PTK7/CCk-4) also leads to
stereocilia orientation defects when mutated in mice (
36). The
mouse mutants
Spin cycle (
Scy) and
Crash (
Crsh) also affect
PCP (
37) and lead to misorientation of OHCs. Although other
mouse mutants, in genes such as
Myo7a and
Cdh23 (see later),
result in disorganized stereocilia bundles, they do not appear
to be directly involved in PCP, which occurs before stereocilia
develop.
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HAIR CELL MAINTENANCE
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Many human and mouse hearing and/or balance mutations lead to
defects in the development or architecture of hair cell sterocilia.
These specialized structures, when deflected by transmitted
sound, directly lead to gating of AHC ion channels, potassium
influx and cell depolarization. The genes that underlie the
various forms of Usher's Syndrome (USH) have provided particular
insights into stereocilia development and/or maintenance. Of
the 11 USH loci, seven have been molecularly cloned (several
of these also cause non-syndromic hearing loss). Most of these
genes are ‘structural’ in nature and include
MYO7A,
HARMONIN,
CDH23,
PCDH15,
USH2A and
USH3 (
38–
46). Many
of these proteins have recently been shown to interact with
each other. For example, mutations in the
SANS gene were recently
identified as causing USH1G (
47) and the
Jackson shaker mutation
in mice (
48). These alterations lead to stereocilia bundle disorganization.
The
SANS gene product interacts with another USH protein, HARMONIN
(USH1C). HARMONIN, in turn, interacts with MYOSIN7A and CADHERIN23
(CDH23), two additional USH proteins (
49). Recently the
Deaf circler and
Deaf circler 2 mouse mutants have also been shown
to result from mutations in
Harmonin (
50). Most USH genes encode
proteins with PDZ domains (a common motif for protein–protein
interaction). In this context, it is interesting to note that
the
Whirler mouse mutant (in which hair cells degenerate) was
recently shown to result from mutations in a PDZ protein, Whirlin
(
51,
52). This gene is also responsible for DFNB31 in humans,
and plays a role in stereocilia elongation through actin polymerization.
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ION FLUX
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Ion flux is also critical for hearing and for AHC survival.
Overexposure to K
+ leads to prolonged depolarization, and in
time is toxic. Several hearing and/or balance mutations in mouse
lead to hair cell death owing to ion toxicity. For example,
mutations in tight junctions and gap junctions are thought to
lead to ion toxicity in HCs, resulting in postnatal hair cell
death (
53–
55). The dynamics of these degenerative processes
have been recently examined in a series of mouse models. Defects
in the gap junction protein CONNEXIN 26 (CX26/GJB2,
DFNB1) are
the leading cause of sporadic non-syndromic hearing loss in
Caucasians (
56–
58). This gene has been targeted by conditional
deletion in the mouse inner ear (
59), and has also been overexpressed
as a dominant-negative transgene (
60). In both of these models
SCs die, followed by hair cell death around P14, and there is
an eventual collapse of the organ of Corti, most likely due
to problems in potassium homeostasis. A similar phenotype has
been observed in
Connexin30 knockout mice (
61). Mouse models
in which the gene encoding the tight junction protein Claudin14
(
DFNB26 in humans) is deleted also show progressive loss of
AHCs by 3 weeks of age, possibly through loss of a cation barrier
(
55).
Three TF genes have been implicated in hair cell maintenance/survival: when Pou4f3 (Brn3c) is knocked out, it results in a failure of hair cell maturation late in embryonic development (62). Mutations in Gfi1 appear to result in a similar phenotype to Pou4f3 (63). Gfi1 is the mouse ortholog of the Drosophila gene senseless, and its expression is directly dependent on Pou4f3 (64). The third of these TF genes is Barhl1, which was mentioned earlier as being potentially interconnected with the Math1 pathway (Figs 2 and 3). Its expression is first detected in the cochlea at E14.5 and it is still expressed in AHCs at P2 (65). Barhl1 null mice exhibit early and progressive hearing loss. However, these mice continue to express Math1, Pou4f3, Myo6 and Myo7a, indicating that Barhl1 is more likely to play a role in HC maintenance than initiation of HC differentiation. By P6, OHCs in the apical region of the null mutants show stereocilia misalignment and disorganization leading to progressive deafness.
Genes that are involved in Mendelian forms of hearing loss, such as those mentioned earlier, may provide insights into the more complex and common later onset forms. One interesting example is the Cdh23 gene, mutations in which disrupt stereocilia in USH1D, DFNB12 and the Waltzer mouse mutant (40,41,66). A single-nucleotide polymorphism (SNP) in Cdh23 was found to act as a genetic modifier of the mouse Deaf waddler mutation in age-related hearing loss (AHL) (67). This SNP (which leads to a synonomous codon substitution) is sufficient to cause exon skipping in the Cdh23 gene. Subtle genetic alterations in known deafness loci, such as those found in Cdh23, may prove to be important discriminators of risk for late onset hearing loss in humans. Interestingly, Cadherin23 has now also been shown to be a component of hair cell stereocilia tip links (a filamentous linkage between the ends of adjacent stereocilia) (68,69). Defining the components of tip links has been a long sought goal of auditory biologists that has at last been achieved.
We are beginning to gain insights into hair cell maintenance and stereocilia structure from mouse and human mutations. However, identifying the gene that encodes the hair cell-specific, mechanotransduction potassium channel has proved elusive. The presence of only a small number of channels on a small population of cells has made this biochemically difficult. However, recent work in zebrafish raises the hope that this might prove tractable. By employing a combination of molecular biology and bioinformatics approaches, Sidi et al. (70) were able to isolate the zebrafish ortholog of the Drosophila nompC (no mechanoreceptor potential C) gene. This channel is expressed in all five sensory patches of the zebrafish embryonic inner ear. Morpholino-directed knockdown of this gene leads to deafness, and failure to respond to acoustic stimuli. Hair cells appear morphologically normal, but lack channel activity. NompC is a member of the TRP superfamily of channels, transient receptor potential channels implicated in a variety of sensory processes. However, the zebrafish gene shares only 45% identity with its Drosophila ortholog, and conventional computational homology searches do not identify any unequivocal orthologs in the mouse or human genomes. Thus, the search for the mammalian channel continues.
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STEM CELLS
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It is still unclear whether a stem cell population exists in
the SE during late mammalian embryogenesis or in early postnatal
life. Many, generally inconclusive, attempts have been made
to identify such a cell type. Most recently, Li
et al. (
71) reported a possible stem cell population in adult mouse
utricles (a component of the inner ear that senses changes in
movement). These cells appeared to have pluripotent potential
and exhibited many of the characteristics that might be expected
of inner ear stem cells. In a parallel study, the same group
took on the even more daunting task of differentiating embryonic
stem cells (ES) toward a hair cell fate (
72). ES cells were
cultured in the presence of EGF and IGF-1, and subsequently
in bFGF. Encouragingly, the resulting cultures contained cells
that expressed a wide range of HC-specific markers, but these
also showed expression of some SC markers. This may indicate
that a mixed population is present and/or the cells were not
fully differentiated. Transplantation of these mouse cells to
the chick inner ear resulted in some hopeful signs of hair cell
differentiation. The possibilities of stem cell therapies are
exciting, but the current state-of-the-art for inner ear ES
cell differentiation seems rather hit or miss at present. Various
combinations of treatments are used in the hope that one will
produce the correct spectrum of markers. It appears likely that
a more directly engineered approach may be required in the future
in order to achieve pure populations. Nevertheless, it is clear
that differentiation of stem cells is a route that many investigators
will continue to pursue, and one that holds great promise for
possible replacement therapy.
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GENOMIC APPROACHES TO AHC FUNCTION
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With the exception of some useful but small scale Expressed
Sequence Tag (EST) projects (
73) the major genomic contribution
to this field has been through microarray-based gene expression
profiling. These present a considerable technical challenge,
because the inner ear is very small, necessitating either large-scale
tissue procurement or extremely robust RNA amplification methods.
It also contains a wide diversity of cell types, which complicates
the expression analysis. As one means to partially circumvent
these problems, Rivolta
et al. (
74) conducted an analysis
of gene expression in a conditionally immortal mouse cochlear
cell line. Likewise, Chen and Corey (
75) used postnatal mouse
cochlear samples to analyze major gene expression changes, and
as the starting point for an inner ear gene expression database
(
76). Both of these studies constitute important base line profiles
of inner ear gene expression. Our group has investigated gene
expression in pure populations of SE from the chicken inner
ear (
77). The chicken utricle SE is in a constant cycle of apoptosis
and regeneration, whereas the cochlear SE is quiescent (if the
hair cells are not damaged). We initially compared gene expression
between these two SEs and identified >100 genes that showed
significant differences. Of these,
80 were TF genes identified
using a cross-species TF microarray that we developed (
78).
We have now extended these observations to a large-scale study
of TF gene expression changes that occur in chicken cochlear
and utricle SEs as they regenerate in response to different
forms of damage. These have been compared to data derived from
damaged mouse SE to identify similarities and differences. These
time courses of gene expression have allowed us to identify
known pathways of gene expression, as well as a core group of
TF genes that are expressed in all chicken regenerative timecourses
(unpublished data). In addition to these profiling studies we
have also embarked upon RNA interference studies to knockdown,
phenotypically characterize and expression profile the effects
of specific TF genes in chicken SE.
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FUTURE DIRECTIONS
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It is likely that ‘solving’ the developmental and
regenerative gene ‘wiring diagram’ for AHCs will
require connecting the currently known parts of the puzzle and
discovering as yet unknown components. Hopefully, this will
not occur one gene at a time. It seems likely that the elegant
model systems that have been so painstakingly constructed and
studied to date (and in particular, the ever increasing number
of mouse mutants and knockouts), will prove amenable to more
large scale technologies, such as microarray analysis, high
throughput RNAi knockdowns, proteomics methods and the application
of new genomics approaches such as chromatin IP to define downstream
targets of TFs. These technologies should provide the types
of insights that will better inform current efforts towards
gene and/or stem cell therapies for AHC damage.
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ACKNOWLEDGEMENTS
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We thank Dr Anne M. Bowcock for her critical reading of this
manuscript. We are particularly grateful for financial support
from the National Organization for Hearing Research Foundation
and from the NIDCD of the NIH for grant RO1-DC005632.
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FOOTNOTES
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* To whom correspondence should be addressed. Tel: +1 3147473265; Email:
lovett{at}genetics.wustl.edu
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TOP
ABSTRACT
DEVELOPMENTAL ANATOMY OF AHCs