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1. Influence of Hoxa11 and Hoxd11 on Calcaneus Growth and Ossification

   Bhavsar, Avani ; Goldman, Samuel ; Kjosness, Kelsey M ; Schuetz, Emily ; Kistler, Sabrina ; Thompson, Ryan ; Reno, Philip L ( May 2021 , The FASEB journal)

   null (Ed.)

   Hox genes are key developmental patterning genes that impact segmental identity and skeletal patterning. While Hox11 genes are known to be expressed around the developing calcaneus bone of the ankle, previous studies on mice with Hox11 mutations have indicated that calcaneus morphology is not affected until both Hoxa11 and Hoxd11are knocked out, at which point the calcaneus and talus fail to form.The pisiform bone, a wrist bone that is paralogous to the calcaneus, exhibits substantial morphological and growth plate alterations with Hox11 mutations. We have previously shown that some length differences are present in the adult calcanei of mice with Hoxa11 and Hoxd11 loss-of-function mutations. The present study investigates whether or not the calcaneus growth plate is altered by Hoxa11 and Hoxd11 loss-of-function mutation. We conducted histological analysis of the calcaneus growth plate in juvenile mice with Hoxa11 and Hoxd11 loss-of-function mutations and compared them to ossification patterns observed in whole-mount specimens that were cleared and stained with alizarin red and alcian blue to visualize bone and cartilage, respectively. Histological analysis reveals that early calcaneus growth plates preserve the hypertrophic and proliferative growth plate zones. This is in contrast to the pisiform and likely a result of Hoxc gene expression in the hind limb but not the forelimb. The shape of the epiphyseal cartilage, however, differs greatly in mice with a combined three loss-of-function alleles between Hoxa11 and Hoxd11. In these mice, the calcaneus epiphyseal cartilage is conical shaped with an elongated region of reserve zone chondrocytes. The ossification front and calcaneal tendon insertion are also altered compared to wild type specimens. The first evidence of calcaneal epiphysis ossification appears at P9 in some Hox11 mutant mice, while it typically appears at P11 in wild type specimens. By P17, the epiphysis appears to be larger in specimens with both Hoxa11 and Hoxd11 mutations compared to wild type. These results indicate that the calcaneus growth plate is more resilient to Hox11 mutations than the pisiform, but that the calcaneus exhibits morphological changes and evidence of altered ossification timing with fewer loss-of-function alleles than identified by previous studies. 

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2. Morphological Changes in Calcanei of Mice with Hoxa11 and Hoxd11 loss-of-function mutations

   Goldman, Samuel ; Bhavsar, Avani ; Kjosness, Kelsey M ; Kistler, Sabrina ; Schuetz, Emily ; Stephens, Nicholas ; Ryan, Timothy M ; Reno, Philip L ( May 2021 , The FASEB journal)

   null (Ed.)

   Hox11 genes are expressed around the developing wrist and ankle and are known to substantially impact pisiform shape and length in mice. The calcaneus is a tarsal bone that is paralogous to the pisiform in the wrist, but previous descriptions of mice with Hox11 mutations have suggested that little morphological change takes place unless Hoxa11 and Hoxd11 are both knocked out, at which point the calcaneus fails to form. However, these studies primarily relied on cleared and stained whole-mount specimens which limit resolution of morphological features. This study seeks to determine if calcaneus morphology is altered by three or fewer loss-of-function Hoxa11 and Hoxd11 alleles. We obtained microCT scans of 8 week old mice and compared calcaneus morphology in wild type mice and mice with one, two, and three Hoxa11 and Hoxd11 loss-of-function alleles. We used auto3dgm to conduct a 3D geometric morphometric analysis of shape variation using surface semi-landmarks. Principle components (PC) analysis indicates that calcaneus morphology is altered in mice with Hoxa11 and Hoxd11 loss-of-function mutations. PC1 accounts for 35.4% of shape variation and results from changes to the width and height of the calcaneal neck and shape of peroneal tubercle/process. PC2 accounts for 11.9% of shape variation and results from changes to the width of the calcaneal tuberosity and height of the posterior talar facet. Most specimens with either combination of three out of four Hoxa11 and Hoxd11 loss-of-function alleles cluster together. The other genotypes form a gradient of morphological change with WT, Hoxd11 heterozygotes, and Hoxd11 knockouts being most similar to each other and Hoxa11 heterozygotes, Hoxa11 knockouts, and heterozygotes for both genes being most similar to each other. These results suggest that Hox11 loss-of-function mutations result in altered calcaneus morphology and Hoxa11 and Hoxd11 loss-of-function mutations alter the shape of the calcaneus in different ways when fewer than three alleles are knocked out. 

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3. Ontogenetic transformation of the cartilaginous nasal capsule in mammals, a review with new observations on bats

   https://doi.org/10.1002/ar.25152  

   Smith, Timothy D. ; Ruf, Irina ; DeLeon, Valerie B. ( January 2023 , The Anatomical Record)

   The nasal capsule, as the most rostral part of the chondrocranium, is a critical point of connection with the facial skeleton. Its fate may influence facial form, and the varied fates of cartilage may be a vehicle contributing to morphological diversity. Here, we review ontogenetic changes in the cartilaginous nasal capsule of mammals, and make new observations on perinatal specimens of two chiropteran species of different suborders. Our observations reveal some commonalities betweenRousettus leschenaultiiandDesmodus rotundus, such as perinatal ossification of the first ethmoturbinal. However, inRousettus, ossification of turbinals is demonstrated as either perichondrial or endochondral. InDesmodus, perichondrial and endochondral ossification of the posterior nasal cupula is observed at birth, a part of the nasal capsule previously shown to persist as cartilage into infancy inRousettus. Combined with prior findings on cranial cartilages we identify several diverse transformational mechanisms by which cartilage as a tissue type may contribute to morphological diversity of the cranium. First, cartilage differentiates in an iterative fashion to increase nasal complexity, but still retains the capacity for later elaboration via de novo bone emanating outward before or after cartilage ossifies. Second, cartilage acts as a driver of growth at growth centers, or via interstitial growth (e.g., septal cartilage). Finally, cartilage as a tissue may influence the timing of ossification and union of the facial and basicranial skeleton. In particular, cartilage at certain points of ontogeny may “model” via selective resorption, showing some similarity to bone.

    

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4. Fissures, folds, and scrolls: The ontogenetic basis for complexity of the nasal cavity in a fruit bat ( Rousettus leschenaultii )

   https://doi.org/10.1002/ar.24488  

   Smith, Timothy D. ; Curtis, Abigail ; Bhatnagar, Kunwar P. ; Santana, Sharlene E. ( July 2020 , The Anatomical Record)

   Mammalian nasal capsule development has been described in only a few cross‐sectional age series, rendering it difficult to infer developmental mechanisms that influence adult morphology. Here we examined a sample of Leschenault's rousette fruit bats (Rousettus leschenaultii) ranging in age from embryonic to adult (n= 13). We examined serially sectioned coronal histological specimens and used micro‐computed tomography scans to visualize morphology in two older specimens. We found that the development of the nasal capsule inRousettusproceeds similarly to many previously described mammals, following a general theme in which the central (i.e., septal) region matures into capsular cartilage before peripheral regions, and rostral parts of the septum and paries nasi mature before caudal parts. The ossification of turbinals also generally follows a rostral to the caudal pattern. Our results suggest discrete mechanisms for increasing complexity of the nasal capsule, some of which are restricted to the late embryonic and early fetal timeframe, including fissuration and mesenchymal proliferation. During fetal and early postnatal ontogeny, appositional and interstitial chondral growth of cartilage modifies the capsular template. Postnatally, appositional bone growth and pneumatization render greater complexity to individual structures and spaces. Future studies that focus on the relative contribution of each mechanism during development may draw critical inferences how nasal morphology is reflective of, or deviates from the original fetal template. A comparison of other chiropterans to nasal development inRousettuscould reveal phylogenetic patterns (whether ancestral or derived) or the developmental basis for specializations relating to respiration, olfaction, or laryngeal echolocation.

    

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5. Extracellular matrix regulation of stress response genes during larval development in Caenorhabditis elegans

   https://doi.org/10.1093/g3journal/jkac221  

   Chandler, Luke M. ; Choe, Keith P. ; Lee, ed., S. S. ( August 2022 , G3 Genes|Genomes|Genetics)

   Mutation or loss of 6 extracellular matrix collagen genes disrupts annular furrows in adult C. elegans cuticles, causes a wide “Dumpy” body morphology, and activates osmotic, detoxification, and antimicrobial defense genes. High environmental osmolarity reduces internal turgor pressure, physically distorts the epidermis, and activates the same stress responses. Collagen gene mutations that cause Dumpy without furrow disruption do not activate stress responses. These results are consistent with an extracellular damage sensor associated with furrows in the adult cuticle that regulates environmental stress responses in adjacent cells. Several cuticle characteristics change between molts, but all stages have annular furrows and express furrow collagen genes. We compared body shape, furrow organization imaged with differential interference contrast microscopy, and stress response gene expression in furrow collagen gene mutants at all postembryonic stages. We find that most body shape and furrow disorganization phenotypes start at the L3 stage and increase in severity with each molt afterwards. Stress response genes were induced the strongest in adults, correlating with the greatest Dumpy and furrow phenotypes. Although weaker than in adults, osmolyte transporter gene hmit-1.1 and antimicrobial gene nlp-29 were also induced in some early larvae that had weak or undetectable cuticle phenotypes. Our data are consistent with progressive cuticle phenotypes in which each new cuticle is at least partially directed by organization of the former cuticle. Gene expression and cuticle data support the role of furrow disruption as a signal in L4 larvae and adults, but also suggest a role for other cuticle organization or epidermal cell effects in early larvae.

    

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