Morphological Evolution Of The Scapula In Tree Squirrels, Chipmunks, And Ground Squirrels (Sciuridae): An Analysis Using Thin‐Plate Splines

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137581/1/evo01274.pd

Stasis of functionally versatile specialists

A classic hypothesis posits that lineages exhibiting long‐term stasis are broadly adapted generalists that remain well‐adapted despite environmental change. However, lacking constraints that steepen adaptive peaks and stabilize the optimum, generalists’ phenotypes might drift around a broad adaptive plateau. We propose that stasis would be likely for morphological specialists that behave as ecological generalists much of the time because specialists’ functional constraints stabilize the optimum, but those with a broad niche, such as generalists, can persist despite environmental change. Tree squirrels (Callosciurinae and Sciurini) exemplify ecologically versatile specialists, being extreme in adaptations for forceful biting that expand rather than limit niche breadth. Here, we examine the structure of disparity and the evolutionary dynamics of their trophic morphology (mandible size and shape) to determine if they exhibit stasis. In both lineages, a few dietary specialists disproportionately account for disparity; excluding them, we find compelling evidence for stasis of jaw shape but not size. The primary optima of these lineages diverge little, if at all over approximately 30 million years. Once their trophic apparatus was assembled, their morphological specialization steepened the slopes of their adaptive peak and constrained the position of the optima without limiting niche breadth.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156132/2/evo13956.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156132/1/evo13956_am.pd

Complexity and integration in the control of inner-ear development

A report on the Sixth Molecular Biology of Hearing and Deafness Conference, Hinxton, UK, 11-14 July 2007

Relationships of diversity, disparity, and their evolutionary rates in squirrels (Sciuridae)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111786/1/evo12642.pd

Hyaluronic Acid Enhances Gene Delivery into the Cochlea

Abstract Cochlear gene therapy can be a new avenue for the treatment of severe hearing loss by inducing regeneration or phenotypic rescue. One necessary step to establish this therapy is the development of a safe and feasible inoculation surgery, ideally without drilling the bony cochlear wall. The round window membrane (RWM) is accessible in the middle-ear space, but viral vectors placed on this membrane do not readily cross the membrane to the cochlear tissues. In an attempt to enhance permeability of the RWM, we applied hyaluronic acid (HA), a nontoxic and biodegradable reagent, onto the RWM of guinea pigs, prior to delivering an adenovirus carrying enhanced green fluorescent protein (eGFP) reporter gene (Ad-eGFP) at the same site. We examined distribution of eGFP in the cochlea 1 week after treatment, comparing delivery of the vector via the RWM, with or without HA, to delivery by a cochleostomy into the perilymph. We found that cochlear tissue treated with HA-assisted delivery of Ad-eGFP demonstrated wider expression of transgenes in cochlear cells than did tissue treated by cochleostomy injection. HA-assisted vector delivery facilitated expression in cells lining the scala media, which are less accessible and not transduced after perilymphatic injection. We assessed auditory function by measuring auditory brainstem responses and determined that thresholds were significantly better in the ears treated with HA-assisted Ad-eGFP placement on the RWM as compared with cochleostomy. Together, these data demonstrate that HA-assisted delivery of viral vectors provides an atraumatic and clinically feasible method to introduce transgenes into cochlear cells, thereby enhancing both research methods and future clinical application.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98453/1/hum%2E2011%2E086.pd

Inappropriate p53 Activation During Development Induces Features of CHARGE Syndrome

CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53(25,26,53,54)), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53(25,26,53,54)(/-) embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome

The complex ontogenetic trajectory of mandibular shape in a laboratory mouse

The mouse mandible is a popular model system that continues to be the focus of studies in evo‐devo and other fields. Yet, little attention has been given to the role of postnatal growth in producing the adult form. Using cleared and stained specimens, we describe the timing of tooth and jaw development and changes in jaw size and shape from postnatal day 1 (p1) through weaning to adulthood. We found that tooth development is relatively advanced at birth, and that the functional adult dentition is in place by p15 (just before the start of weaning). Shape analysis showed that the trajectory of mandible shape changes direction at least twice between birth and adulthood, at p7 and p15. At each stage there are changes in shape to all tooth‐ and muscle‐bearing regions and, at each change of direction, all of these regions change their pattern of growth. The timing of the changes in direction in Mus suggests there are signals that redirect growth patterns independently of changes in function and loading associated with weaning and jaw muscle growth. A better understanding of these signals and how they produce a functionally integrated mandible may help explain the mechanisms guiding evolutionary trends and patterns of plasticity and may also provide valuable clues to therapeutic manipulation of growth to alleviate the consequences of trauma or disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/101793/1/joa12118.pd

Data from: Relationships of diversity, disparity and their evolutionary rates in squirrels (Sciuridae)

Several theories predict that rapidly diversifying clades will also rapidly diverge phenotypically; yet, there are also reasons for suspecting that diversification and divergence might not be correlated. In the widely distributed squirrel clade (Sciuridae), we test for correlations between per-lineage speciation rates, species richness, disparity and a time-invariant measure of disparity that allows for comparing rates when evolutionary modes differ, as they do in squirrels. We find that species richness and speciation rates are not correlated with clade age or with each other. Disparity appears to be positively correlated with clade age because young, rapidly diversifying Nearctic grassland clades are strongly pulled to a single stable optimum but older, slowly diversifying Paleotropical forest clades contain lineages that diverge along multiple ecological and morphological lines. That contrast is likely due to both the environments they inhabit and their phylogenetic community structure. Our results argue against a shared explanation for diversity and disparity in favor of geographically mediated modes of speciation and ecologically mediated modes of phenotypic evolution