Biomedical subjects
Publications and source records attributed to Malcolm Maden.
In the regenerating amphibian limb, positional information has traditionally been considered in terms of short-range cell-cell interactions, not long-range diffusion gradients. A molecule discovered in a differential screen of regenerating limbs turns out to be precisely such a cell surface component, the newt ortholog of mouse CD59.
Retinoic acid, acting through the nuclear retinoic acid receptor beta2 (RARbeta2), stimulates neurite outgrowth from peripheral nervous system tissue that has the capacity to regenerate neurites, namely, embryonic and adult dorsal root ganglia. Similarly, in central nervous system tissue that can regenerate, namely, embryonic mouse spinal cord, retinoic acid also stimulates neurite outgrowth and RARbeta2 is upregulated. By contrast, in the adult mouse spinal cord, which cannot regenerate, no such upregulation of RARbeta2 by retinoic acid is observed and no neurites are extended in vitro. To test our hypothesis that the upregulation of RARbeta2 is crucial to neurite regeneration, we have transduced adult mouse or rat spinal cord in vitro with a minimal equine infectious anaemia virus vector expressing RARbeta2. After transduction, prolific neurite outgrowth occurs. Outgrowth does not occur when the cord is transduced with a different isoform of RARbeta nor does it occur following treatment with nerve growth factor. These data demonstrate that RARbeta2 is involved in neurite outgrowth, at least in vitro, and that this gene may in the future be of some therapeutic use.
Recent studies have shown that the pharyngeal endoderm plays a critically important role in directing the development of the pharyngeal region of the vertebrate embryo. We have, however, had few insights into how the pharyngeal endoderm itself is patterned. Recently, several studies have suggested that retinoic acid is required for the development of the pharyngeal endoderm. To study this proposal in greater depth, we have examined the development of the pharyngeal endoderm in the absence of retinoid signalling, by using the vitamin A- deficient (VAD) quail model system. We find in early stages that, in the absence of retinoids, this territory extends further caudally than normal. Furthermore, as development proceeds, we find that the first pouch invariably forms, that the second pouch is abnormal, and that the third and fourth pharyngeal pouches never form. We do find, however, that dorsoventral patterning of the pharyngeal endoderm is unaffected. Finally, we have examined the expression patterns of RALDH2 before and during early development of the pharyngeal pouches. We find that this enzyme is expressed adjacent to the pharyngeal endoderm in tissues around the regressing anterior intestinal portal and that from stage 12 onward its anterior limit of expression lies at the level of the second pouch. This finding helps explain why the first pouch always forms in the absence of retinoids, and why defects are seen starting with the second and most evidently in the caudal pouches.
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Endogenous retinoids have been implicated in alveologenesis in both the rat and the mouse, and exogenous retinoic acid (RA) can reverse or partially reverse experimental emphysema in adult rat and mouse models by an unknown mechanism. In this study, we examine the cellular and molecular biology of retinoid signaling during alveologenesis in the mouse. We describe the temporal and spatial expression of the retinoid binding proteins CRBP-I, CRBP-II, and CRABP-I using RT-PCR and immunohistochemistry. We identify the retinoic acid receptor isoforms RAR-alpha 1, RAR-beta 2, RAR-beta 4, and RAR-gamma 2 and describe their temporal and spatial expression using RT-PCR and in situ hybridization. We demonstrate that both retinoid binding proteins and RAR isoforms are temporally regulated and found within the alveolar septal regions during alveologenesis. These data support a role of dynamic endogenous RA signaling during alveolar formation.
Alveoli are formed postnatally in the rat, mouse, and human. The molecular signals controlling the patterning of this developmental process are not well understood. Here we describe immunohistochemical studies that label proliferating alveolar wall cells which suggest two distinct patterns of alveologenesis: (1) a low grade, peripheral subpleural parenchymal process which occurs from P1 through to P15; and (2) a dramatic increase in central cell proliferation from P4 which is complete by P15, corresponding to the well described period of alveolar septation. We describe the temporal and spatial expression of the retinoid-synthesizing enzymes Aldh-1 and Raldh-2 in the postnatal mouse lung. Both enzymes are upregulated during the period of maximal alveolar wall cell proliferation. Aldh-1 is located in the bronchial epithelium and alveolar parenchyma, and Raldh-2 is restricted to the bronchial epithelium and pleural mesothelial cells. High-pressure liquid chromatography (HPLC) reveals that rapidly septating lungs have relatively simple chromatographic profiles; in contrast, the adult lungs have a complex profile that includes many novel retinoids. These data suggest two patterns of alveolar proliferation with temporal and spatial association of the enzymes Aldh-1 and Raldh-2 and a dynamic role for different retinoids in both the septating and adult mouse lung.
Here I describe the situation which led up to the descriptions of the dramatic effects of retinoids on the regenerating amphibian limb. The original papers from an Indian group were published in relatively obscure journals but thanks to literature searches were made available for reading. Repetition of this work and its publication in widely read journals spawned the new field of research on the role of retinoids in developing and regenerating limbs.